NON-HUMAN PRIMATE IMMUNE TOLERANCE COOPERATIVE STUDY GROUP Release Date: January 25, 2001 RFA: RFA-AI-01-006 (This RFA has been reissued, see RFA-AI-06-018) National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov) National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov) Letter of Intent Receipt Date: June 11, 2001 Application Receipt Date: July 17, 2001 PURPOSE The Division of Allergy, Immunology, and Transplantation (DAIT) of the National Institute of Allergy and Infectious Diseases (NIAID) and the Division of Diabetes, Endocrinology, and Metabolic Diseases (DDEMD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invite applications from single institutions and consortia of institutions to participate in the Non-Human Primate Immune Tolerance Cooperative Study Group (NHPCSG). The NHPCSG is a multi-center, cooperative research program focused on the study of immune tolerance in non-human primate models of kidney and islet allograft rejection, asthma and allergic diseases and autoimmune diseases. The goals of this research program are to: evaluate the safety and efficacy of novel tolerance induction regimens; elucidate the mechanisms of the induction, maintenance and loss of tolerance; and develop and validate biomarkers for induction, maintenance, and loss of tolerance in these immune-mediated disorders. For purposes of this Request for Applications (RFA), immune tolerance is defined as a lack of a pathogenic immune response to allogeneic, environmental, or self-antigens in the absence of ongoing immunosuppressive therapy. Tolerance may be induced by a variety of approaches, including: clonal deletion, clonal anergy, immune deviation, or suppression. Projects should be designed to meet these goals in established and new non-human primate models of kidney and islet transplantation, asthma and allergic diseases, and autoimmune diseases. Because the ultimate purpose of this RFA is to develop candidate tolerogenic approaches for the treatment of immune-mediated diseases in humans, the sponsors expect that there will be reciprocal communication between the NHPCSG and the Immune Tolerance Network and Type 1 Diabetes TrialNet. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS led national activity for setting priority areas. This RFA, Non-Human Primate Immune Tolerance Cooperative Study Group, is related to Diabetes and Chronic Disabling Conditions. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private institutions, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible to apply. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The administrative and funding mechanisms to be used to undertake this program will be the Cooperative Agreement (U01) and the Multi-project Cooperative Agreement (U19), "assistance" mechanisms, rather than "acquisition" mechanisms. Under the cooperative agreement, the National Institutes of Health (NIH) purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the research will be shared among the awardees and the NIH Coordinators. Essential elements of the multi-project cooperative agreement mechanism (U19) include: 1. A minimum of three interrelated individual research projects organized around a central theme; 2. Collaborative efforts and interaction among independent projects and their investigators to achieve a common goal; 3. A single Principal Investigator who will be scientifically and administratively responsible for the group effort; 4. A single applicant institution that will be legally and financially responsible for the use and disposition of funds awarded; and 5. Where necessary, support for "Core" resources or facilities, each of which shall be utilized by at least two research projects in order to facilitate the research effort. Details of the responsibilities, relationships, and governance of a study funded under a cooperative agreement are discussed later in this document under the section "Terms and Conditions of Award." The total project period for applications submitted in response to this RFA may not exceed five years. FUNDS AVAILABLE The estimated total funds (direct and facilities and administrative (F&A)) available for the first year of support for this RFA will be between $4,000,000 and $6,000,000. In fiscal year 2002, the NIH plans to make six to seven awards related to this RFA. This level of support is dependent on (1) the receipt of a sufficient number of applications of high scientific merit, (2) the relative proportions of U01 and U19 applications, and (3) the availability of funds. Applications for U01 awards may not request budgets in excess of $500,000 total (direct and F&A) first-year costs. Applications for U19 awards may not request budgets in excess of $1,000,000 total first-year costs. The NIH Grants Policy governing grants administration and management will apply. Although this program is provided for in the financial plans of the sponsoring institutes, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and availability of funds. RESEARCH OBJECTIVES Background The cosponsors of this RFA support research focused on immune tolerance, immune- mediated diseases, diabetes, and kidney diseases, including the development of improved therapies to prevent these diseases and treat their complications. Supported research also focuses on the use of non-human primate models for studies that elucidate human health problems and disease processes. The NIAID and NIDDK have made research on immune tolerance a high scientific priority and. In the fall of 1997, NIAID initiated a scientific planning process designed to accelerate research in this area. The broad-based, long- range NIAID Plan for Research on Immune Tolerance is available at: http://www.niaid.nih.gov/publications/immune/bookcover.htm The NIAID Expert Panel for Research on Immune Tolerance enthusiastically endorsed the conceptual framework, scope and timeliness of the plan and encouraged the NIAID to take a leadership role in designing and directing major research programs focused on immune tolerance, particularly with respect to the treatment of human disease. Two subsequent expert panels, the NIAID Expert Panel on Ethical Issues in Clinical Trials of Transplant Tolerance and the Expert Review Panel for NIAID's Extramural Transplantation Research Program, identified non-human primate tolerance research as an essential step to provide "...critical data on safety, toxicity and potential efficacy that can not be obtained ethically in human clinical trials." In 1998, NIAID established a program in non-human primate models of kidney and islet transplantation using the NIH Director’s 1% Transfer Authority Funds. In 1999, this effort was expanded though an RFA, co-sponsored by NIAID, NIDDK, and the National Center for Research Resources (NCRR). The current, RFA seeks to expand support for immune tolerance research in kidney and islet transplantation and initiate support for immune tolerance research in non-human primate models of other immune mediated diseases. In September 1997, the Director of National Institutes of Health (NIH) and the Director of NIDDK sponsored - with the co-sponsorship of eight other Institutes and Centers of NIH - a unique landmark symposium on "Diabetes Mellitus: Challenges and Opportunities." This symposium brought together over 150 investigators to develop recommendations on how diabetes research should be intensified to close research gaps, take advantage of new technologies, and capitalize on highly promising research leads and advances. One recommendation was the development of and access to larger animal models of diabetes. Subsequently the Congress established the Diabetes Research Working Group to develop a strategic research plan for NIH-funded diabetes research. This plan, Conquering Diabetes: A Strategic Plan for the 21st Century, Report Summary and Recommendations, can be found at (http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm). This panel identified research on autoimmunity and the beta cell as one of five extraordinary opportunities and recommended expanded research on islet transplantation and immune intervention as well as support of centers using large animal models to test new therapies for type 1 diabetes. 1. Transplantation Transplantation is now routine therapy for end-stage renal disease, with one- year graft survival approaching 90% using standard immunosuppressive therapy. However, long-term graft survival has improved only slightly since the early 1980s, with about 62% of cadaveric kidneys surviving five years post-transplant. For other organs (e.g., heart, liver, lung and pancreas), graft survival rates are similar. While new immunosuppressive drugs have reduced acute rejection in the first year post-transplant, it is clear that these therapeutic improvements have only marginally altered long-term clinical outcomes. Therefore, current attention has focused on the potential for donor-specific immune tolerance to achieve long-term graft survival without non-specific, life- long immunosuppressive therapies that have deleterious and often life- threatening side effects. Although certain promising tolerogenic regimens have been shown to induce donor-specific immune tolerance in animal models, and are being tested in humans for the treatment of selected autoimmune diseases, these approaches have not been rigorously evaluated in the transplant setting. Both the Expert Panel on Immune Tolerance and the Expert Panel on Ethical Issues in Clinical Trials of Transplant Tolerance recommended that NIAID pursue tolerance research in non-human primate models of kidney and islet transplantation as a prelude to human clinical trials. These recommendations were reinforced and expanded by the extraordinary opportunities as presented in the Congressionally- requested report "Conquering Diabetes: A Strategic Plan for the 21st Century." 2. Asthma and Allergic Diseases Asthma and allergic diseases, including allergic rhinitis, atopic dermatitis, urticaria and anaphylaxis, are among the major causes of illness and disability in the United States. NIAID vigorously pursues research on asthma and allergic diseases by fostering investigator-initiated projects and by supporting a national network of research centers, cooperative clinical studies, and demonstration and education research projects. The cause, pathogenesis, diagnosis, treatment, and prevention of asthma and allergic diseases are major areas of emphasis for the NIAID Division of Allergy, Immunology, and Transplantation, and recent research advances have led to a better understanding of the pathogenesis of these diseases. Nevertheless, translation of the basic research findings into new approaches to treatment and prevention of asthma and allergic diseases has been hampered by the lack of animal models that accurately simulate the important features of human disease. This is particularly important with respect to asthma, for which there is increasing epidemiological and clinical evidence that early life changes in immune system function contribute to the development of the disease. Because of the similarity in the development of the non-human primate immune system to that of man, there is a need for non-human primate models that will facilitate the investigation of the early life origins of asthma and the tracking of changes in immune function that occur as the disease progresses. The Expert Panel convened to review the NIAID Extramural Asthma and Allergy research program underscored the limitations of currently available animal models of asthma and suggested that the NIAID support suitable non-human primate models. This can be best accomplished through the coordinated, high quality infrastructure provided by expansion of the NHPCSG. 3. Autoimmune Diseases Autoimmune diseases, which are caused by immune reactions against self-antigens, affect more than five (5) percent of the U. S. population and disproportionately affect women. These diseases are a significant cause of chronic morbidity, costing billions of dollars annually in health care expenses and lost productivity. NIAID supports a program of basic and clinical research in autoimmunity. NIDDK supports basic and clinical research on type 1 diabetes, inflammatory bowel disease and liver and kidney diseases resulting from autoimmune mechanisms. Basic research focuses on: understanding the genetics of autoimmunity, elucidating the mechanisms that underlie self-tolerance, inducing self-tolerance, and characterizing the pathways of immune-mediated tissue destruction. Knowledge gained from basic studies provides the rationale for: developing clinical tests to diagnose autoimmune diseases; therapies to prevent autoimmune diseases; and novel treatments for ongoing disease. Efforts to induce tolerance in autoimmunity have focused primarily on the oral administration of antigens. Oral tolerance can be induced in animal models and is now being evaluated in human diseases, including type 1 diabetes. However, the encouraging responses in animal studies have not been duplicated in recent clinical trials of rheumatoid arthritis and multiple sclerosis. There are a number of promising tolerogenic approaches other than oral tolerance that can be pursued, including: costimulatory blockade, anti-cytokine monoclonal antibodies, hematopoietic stem cell and bone marrow transplantation, and gene transfer-based therapies for cytokine modulation. Expansion of the NHPCSG will follow the recommendation in The Report of the NIH Autoimmune Diseases Coordinating Committee and the Diabetes Research Working Group, which encourage the exploration of therapeutic approaches to autoimmunity in animal models that more faithfully mimic human autoimmune diseases. In addition, the Expert Panel on Immune Tolerance and the Congressional-established Diabetes Research Working Group highlighted the need to evaluate the safety and efficacy of various tolerance induction regimens and agents in non-human primate models of autoimmune diseases. 4. Non-Human Primates Studies of existing and new tolerogenic treatment regimens in non-human primate models of kidney and islet transplantation, asthma and allergic diseases, and autoimmune diseases are critical to the design of scientifically sound and ethically acceptable clinical trials. In addition, non-human primates are especially useful as they closely approximate the human immune system and physiology. Non-human primates also allow collection of important biological samples necessary to validate new non-invasive or minimally invasive diagnostic tests for tolerance, graft function, survival, and rejection, asthma and allergic diseases, and autoimmune diseases. Research Objectives and Scope The purpose of this RFA is to support a multi-site cooperative research program to develop tolerance induction protocols in non-human primate models of immune- mediated diseases. For purposes of this RFA, immune tolerance is defined as a lack of a pathogenic immune response to allogeneic, environmental, or self- antigens in the absence of ongoing immunosuppressive therapy. Tolerance may be induced by a variety of approaches as described below. All participating sites will use uniform controlled study designs and standardized data collection procedures. Specifically, the cooperative research program will design and conduct: 1. Studies on the safety and efficacy of tolerance induction therapies alone, in combination with immunosuppressive therapies, and in combination with immunosuppressive therapy withdrawal. Approaches to immune tolerance may include, but are not limited to, the following: o Co-stimulatory blockade o Cytokine modulation o Clonal deletion o DNA vaccination o Oral administration of antigen o Bone marrow transplantation or donor-specific transfusion o Other approaches such as leukocyte migration blockade, allergen- or autoantigen-specific immunotherapy, and the use of molecularly engineered cells and tissues for deletion or inactivation of pathogenic lymphocytes. 2. Studies of the underlying mechanisms of action of the therapeutic approaches being evaluated, including changes in immune response and function and measures of the induction, maintenance, and loss of donor-specific tolerance. Possible approaches to mechanistic studies include, but are not limited to, the following: o Quantitation of alloreactive, autoreactive, or allergen-specific T lymphocytes o Analysis of alloreactive, autoreactive, or allergen-specific T cells for gene expression that correlates with functions such as inflammation or homing o Comparison of samples from peripheral blood and urine with those from sites of rejection (for transplantation studies), autoimmune tissue destruction, or pulmonary function. 3. Studies to develop, evaluate, and validate biomarkers of immune tolerance. This includes establishing appropriate measures (e.g., cytokines and/or their receptors, lymphocyte subsets, etc.), selecting appropriate samples (e.g., blood, urine, biopsies, etc.), and selecting appropriate techniques (e.g., quantitative PCR, DNA microarrays, imaging, cellular immune assays, etc.) for routine use. Possible markers include: changes in gene or protein expression in blood, urine or biopsy materials; antibody or cytokine levels in blood, urine or biopsies; or in vitro and in vivo immune responsiveness to antigens as determined by T-cell proliferation, cytotoxic T-cell activity, antibody production, cytokine secretion, and immediate or delayed-type hypersensitivity. This RFA will not provide support for: o Studies in animal models other than non-human primates; o Studies to improve the viability or supply of organs, tissues, or cells for transplantation; o Preliminary development of immune-mediated disease models in non-human primates; or o Xenotransplantation into non-human primates. However, this RFA will provide support for costs associated with the procurement of allogeneic non-human primate islets and kidneys. SPECIAL REQUIREMENTS A. Study Organization 1. Steering Committee A Steering Committee, composed of principal investigators, additional investigators where appropriate, and NIH staff will serve as the main governing body of the NHPCSG. Specific details on the composition of the Steering Committee, its responsibilities, and the establishment of subcommittees are listed under Terms and Conditions of Award, Collaborative Responsibilities. A broad range of scientific and technical expertise is required to carry out the objectives of this RFA, including extensive experience in: immune-mediated diseases; asthma and allergic diseases; autoimmune diseases; transplantation immunobiology and genetics; solid organ, cell, and tissue transplantation; non- human primate models of immune system disorders; molecular and cellular biology, particularly as applied to the identification and evaluation of biomarkers and assay development and validation; research design and statistics; and veterinary care for non-human primates. Each participating member of the Cooperative Study Group must possess scientific expertise in the appropriate areas under the direction of a senior scientist as the Principal Investigator responsible for the scientific, technical and administrative coordination and management of the awardee institution(s). NIH will facilitate collaboration and coordination between the Cooperative Study Group and the Immune Tolerance Network (www.immunetolerance.org). Close coordination among these two research programs will facilitate the development of safety, toxicity, and potential efficacy data from non-human primate models critical to the design and implementation of scientifically sound and ethically acceptable human trials for both existing and new tolerogenic approaches. Close coordination will also enable the application of findings from non-human primates to the clinical setting with respect to important biomarkers and reliable assays to measure tolerance. 2. Data Coordination and Management Each Cooperative Study Group member institution will be responsible for collecting, managing, interpreting, and assuring the quality of data collected on site. Applicants should request support for all data collection and analyses, including a Statistical Coordinator, in their budgets. For collaborative studies and specific data analyses, the Steering Committee will select a Statistical Coordinator from among the member institutions. Applicants wishing to serve as a Data Coordinating Center for collaborative studies should request appropriate levels of support in their budgets. The results of those analyses will be delivered to the Steering Committee which will determine: if and what further analyses should be performed; how the results are interpreted; whether the results impact ongoing data collection, ongoing studies, or future studies; and how the findings should be disseminated. The awardees will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS, PHS, and NIH policies. B. Terms and Conditions of Award The following terms and conditions will be incorporated into the Notice of Grant Award and provided to the Principal Investigator as well as the institutional official at the time of award. These special terms and conditions pertaining to the scope and nature of the interaction between the NIH and the investigators are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. Cooperative agreements are subject to the administrative requirements outlined in OMB circulars A-102 and A-110. All pertinent HHS, PHS, and NIH grant regulations, policies and procedures, with particular emphasis on PHS regulations at 42 CFR Part 52 and HHS regulations at 45 CFR Part 74, are applicable. The administrative and funding mechanisms to be used to undertake this program will be the Cooperative Agreement (U01) and the Multi-project Cooperative Agreement (U19), "assistance" mechanisms, rather than "acquisition" mechanisms. Under the cooperative agreement, the National Institutes of Health (NIH) purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the research will be shared among the awardees and the NIH Coordinators 1. Awardee Rights and Responsibilities Awardees will have primary responsibility for defining the research objectives, approaches, and details of the projects within the guidelines of the RFA and for performing the scientific activities. Specifically, awardees have primary responsibility as described below. Steering Committee Membership and Meeting Attendance Each Principal Investigator and additional investigators where appropriate from a consortium, will serve as a voting member of the Steering Committee and will participate in all scientific decisions. Each Steering Committee member will be responsible for attending all Steering Committee meetings and participating in all other Steering Committee activities, e.g., conference calls, special subcommittee meetings as may be necessary, etc. Applicants are instructed to request funds for travel to Steering Committee meetings in their budgets. Protocol Development and Conduct All Cooperative Study Group institutions, upon acceptance of an award, agree to participate in all studies, including those that involve collaborations with biotechnology and pharmaceutical companies, as specified by the Steering Committee. For all studies implemented by the Cooperative Study Group, the Steering Committee will (1) define the objectives and approaches of treatment protocols, mechanistic studies, and tolerance assay and biomarker development; (2) design the consensus protocols and procedures for study conduct and monitoring; and (3) determine the procedures for data collection and quality control. Furthermore, the Steering Committee will decide which treatment protocols will be conducted at multiple centers and which will be conducted at individual institutions. Cooperative Study Group institutions will be required to accept and implement the studies and data collection procedures approved by the Steering Committee. Studies will proceed into the implementation stage only with the concurrence of the Steering Committee. Publication and Presentation of Study Findings Early publication of major findings is encouraged. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of both the Cooperative Study Group and NIH support. Analyses to be performed using the collective data from the Cooperative Study Group institutions will be determined and directed by the Steering Committee. Cooperative Study Group institutions wishing to perform analyses of local data will inform the Steering Committee of any such analyses prior to initiation in order to avoid duplication. Review and approval by the Steering Committee, or a Publications Subcommittee, will be required for all analyses prior to publication or presentation according to criteria that will be developed by the Steering Committee. Monitoring Study Progress The Steering Committee will establish mechanisms for assessing the performance of the Cooperative Study Group institutions. This includes: quality, accuracy and timeliness of data collection and management; conscientious observance of study requirements; and presentation of study results at joint meetings with the Executive Committee of the Immune Tolerance Network. Federally Mandated Regulatory Requirements The PHS Policy on Humane Care and Use of Laboratory Animals requires that applicant organizations proposing to use vertebrate animals file a written Animal Welfare Assurance with the Office of Laboratory Animal Welfare, establishing appropriate policies and procedures for the humane care and use of live vertebrate animals in research activities supported by the PHS. The PHS policy stipulates that an applicant organization, whether domestic or foreign, bears responsibility for the humane care and use of animals in PHS-supported research activities. All institutions are required to comply, as applicable, with the Animal Welfare Act as amended (7 USC 2131 et sec.) and other Federal statutes and regulations relating to animals. These documents are available from the Office of Laboratory Animal Welfare, National Institutes of Health, Bethesda, MD 20892, (301) 496- 7163, http://grants.nih.gov/grants/olaw/olaw.htm 2. NIH Staff Responsibilities The NIH Coordinators will be the Immunobiology Section Chief, Transplantation Immunobiology Branch, DAIT, NIAID and the Senior Advisor for Diabetes, DDEMD, NIDDK. The NIH Coordinators will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination above and beyond normal program stewardship for grants, as described below. Steering Committee Membership and Meeting Attendance The NIH Coordinators will serve as voting members of the Steering Committee, will attend all Steering Committee meetings, and will participate in other Committee activities, e.g., conference calls, special subcommittees, etc. Protocol Development As members of the Steering Committee, the NIH Coordinators will serve as a resource with respect to the design of treatment protocols and adjunct studies and will assist the Steering Committee in study development. Study Materials The NIH Coordinators, in coordination with the DAIT Office of Clinical Applications, will be responsible for coordinating the acquisition and distribution of study materials to be used in the treatment protocol developed by the consensus of the Steering Committee. The NIH is not responsible for obtaining or distributing solid organs, tissues or cells to be used by the Cooperative Study Group. Monitoring Study Performance The NIH Coordinators will provide assistance to the Steering Committee in the development of mechanisms and procedures for monitoring study performance. This includes: the accuracy, quality, and timeliness of data collection and management; consistency in observing study requirements; and presentation of study results at joint meetings with the Executive Committee of the Immune Tolerance Network. The Government, via the NIH Coordinators, will have access to data generated under this Multi-Project Cooperative Agreement and may periodically review the data and progress reports. NIH Staff may use information obtained from the data for the preparation of internal reports on the activities of the study. However, awardees will retain custody of and have primary rights to all data developed under these awards. Publication and Presentation of Study Findings The NIH Coordinators and other NIH representatives may contribute, through review, comment, analysis, and/or co-authorship, to reporting results of the studies conducted by the Cooperative Study Group to the research community and interested lay organizations. Co-authorship by the NIH staff will be subject to approval in accordance with NIH policies regarding staff authorship of publications resulting from extramural awards. Organizational Changes Certain organizational changes require the prior written approval of the NIH Coordinators. These changes include the addition or replacement of a scientific investigator, affiliate, component, or research base that is associated with this research program. A change in the Principal Investigator, or in any key personnel identified on the Notice of Award, must have the prior written approval of the appropriate NIH Grants Management Specialist in consultation with the NIH Coordinators and representatives of other sponsoring institutes. Program Review The NIH Coordinators will review the progress of the Cooperative Study Group through consideration of annual progress reports, periodic reports on ongoing progress, findings and future plans presented during meetings and conference calls, publications, site visits, etc. This review may include, but is not limited to, compliance with the study protocols, adherence to uniform data collection procedures, and participation in Steering Committee and other subcommittee meetings as necessary. The NIH reserves the right to terminate or curtail the study (or any individual award) in the event of (a) a major breech of any Cooperative Study Group approved protocol, (b) substantive changes in the agreed-upon protocols to which the NIH does not agree, (c) reaching a major study endpoint substantially ahead of schedule with persuasive statistical significance, and (d) failure to meet the collaborative responsibilities as determined by the Steering Committee. 3. Collaborative Responsibilities A Steering Committee will serve as the main governing body of the NHPCSG. At a minimum, the Steering Committee will be composed of the NIH Coordinators and the Principal Investigators of each award. If the awardee is a consortium of institutions, one additional investigator from the consortium will serve on the Steering Committee, on an annual rotating basis, as determined by the protocols under development or implemented. The Steering Committee will meet twice during the first 12 months of the project and annually thereafter. The Steering Committee will select a Chairperson from among the non-Federal members during the first meeting of the Committee, to be convened by the NIH Coordinators. The Steering Committee will be responsible for all major scientific decisions and will have primary responsibility for developing the common treatment protocols, approving the design and implementation of all collaborative studies, facilitating the conduct and monitoring of all studies, analyzing and interpreting collaborative study data, and reporting collaborative study results. Studies will proceed to the implementation stage only with the concurrence of the Steering Committee. The responsibilities of the Steering Committee members are listed above under Terms and Conditions of Award. Cooperative Study Group institutions will be required to accept and implement the studies and data collection procedures approved by the Steering Committee. Studies will proceed into the implementation stage only with the concurrence of the Steering Committee. Subcommittees of the Steering Committee may be established as necessary to provide guidance to the Steering Committee on: assays for tolerance and biomarkers, data collection and analysis, collaboration with investigators outside of the Cooperative Study Group, and reporting and publication of collaborative studies. 4. Arbitration Any disagreement that may arise on scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An arbitration panel will be composed of three members - one selected by the Steering Committee (with the NIH members not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by the NIH, and the third member with expertise in the relevant area and selected by the two prior members. The Arbitration Panel will review any scientific or programmatic issue that is significantly restricting progress. While the decisions of the Arbitration Panel are binding, these special arbitration procedures will in no way affect the awardee's right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45 CFR Part 16. LETTER OF INTENT Prospective applicants are asked to submit, by June 11, 2001, a letter of intent that includes a descriptive title of the overall proposed research; the name, address and telephone number of the Principal Investigator and all collaborators; and the number and title of this RFA. Although the letter of intent is not required, is not binding, does not commit the sender to submit an application, and does not enter into the review of subsequent applications, the information that it contains allows NIH staff to estimate the potential review workload and to plan the review. The letter of intent is to be sent to Dr. Priti Mehrotra at the address listed under INQUIRIES. APPLICATION PROCEDURES Applicants are strongly encouraged to call NIH program staff with any questions regarding the responsiveness of their proposed project to the goals of this RFA. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. Application kits are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email: GrantsInfo@nih.gov. Applications are also available on the World Wide Web at http://grants.nih.gov/grants/forms.htm. Applications must be received by July 17, 2001. For purposes of identification and processing, item 2a on the face page of the application must be marked "YES" and the RFA number "AI-01-006" and the words "Non-Human Primate Immune Tolerance Cooperative Study Group" must be entered on the face page. The RFA label and line 2 of the application should both indicate the RFA number. The RFA label must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-sided photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional exact copies of the grant application and all five sets of any appendix material must be sent to Dr. Priti Mehrotra at the address listed under INQUIRIES. DUE TO THE EXPEDITED NATURE OF THIS RFA, IT IS VERY IMPORTANT TO SEND THESE ADDITIONAL COPIES IN ORDER TO FACILITATE THE PEER REVIEW PROCESS. Applicants from institutions that have a Regional Primate Research Center (RPRC) funded by the NIH National Center for Research Resources may wish to identify these centers as resources for conducting the proposed research. If so, a letter of agreement from the RPRC program director or principal investigator could be included with the application. SPECIFIC INSTRUCTIONS FOR U01 COOPERATIVE AGREEMENT APPLICATIONS If a U01 application submitted in response to this RFA is substantially similar to a grant application already submitted to the NIH for review, but that has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will different review committees review essentially identical applications. Therefore, an application that is essentially identical to one that has already been reviewed cannot be submitted in response to this RFA. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. SPECIAL INSTRUCTIONS FOR U19 COOPERATIVE AGREEMENT APPLICATIONS IN RESPONSE TO THIS RFA Applicants for U19 cooperative agreements must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS (August 2000); this brochure is available via the web at: http://www.niaid.nih.gov/ncn/grants/multibron.htm. Applications that are not received as a single package on the receipt date or that do not conform to the instructions contained in PHS 398 (rev. 4/98) Application Kit (as modified in, and superseded by, the NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS" for U19 awards) will be judged non-responsive and will be returned to the applicant. Current NIH policy permits a component research project of a multi-project grant application to be concurrently submitted as a traditional individual research project (R01) application. If, following review, both the multi-project application and the R01 application are found to be in the fundable range, the investigator must relinquish the R01 and will not have the option to withdraw from the multi-project grant. This is an NIH policy intended to preserve the scientific integrity of a multi-project grant, which may be seriously compromised if a strong component project(s) is removed from the program. Investigators wishing to participate in a multi-project grant must be aware of this policy before making a commitment to the Principal Investigator and awarding institution. However, concurrent submission of a component research project of a multi-project U19 cooperative agreement application as an individual U01 cooperative agreement application to this RFA is prohibited. MINIMUM REQUIREMENTS FOR APPLICATION To promote the development of a collaborative program among the award recipients, a minimum number of issues need to be addressed in the applications, as outlined below. 1. The application must include a broad-based research program designed to evaluate the safety and efficacy of tolerogenic approaches in non-human primate models of asthma and allergic diseases, autoimmune diseases, kidney transplantation, or islet transplantation with the goal of inducing immunosuppression free immune tolerance and delineating the mechanisms involved in the induction, maintenance and loss of tolerance as an integral part of the treatment protocols. U19 applications must contain more than one tolerogenic approach. U01 applications may contain a single tolerogenic approach. The research program shall include the following: a) A discussion of the state-of-the-art of research focused on elucidating the underlying mechanisms of immune tolerance and on evaluating tolerogenic approaches in non-human primate studies and human clinical trials. b) A description of gaps in knowledge and scientific opportunities relevant for the application of tolerogenic approaches to non-human primate studies and human clinical trials. c) A plan to accelerate research on immune tolerance in non-human primate models of immune-mediated diseases, including: o A conceptual framework delineating approaches to tolerance induction and their relevance to human immune-mediated diseases, priorities among the various approaches and the rationale for such priorities, including potentially promising reagents and molecules in development; o A description of promising non-human primate treatment protocols, including the rationale for the selection of tolerogenic approaches and overall study design; and o A description of promising mechanistic studies to be incorporated as an integral part of the non-human primate treatment protocols, including the rationale for the selection of the mechanistic studies, proposed techniques, and the overall design of such studies. o A plan detailing the acquisition and preparation, if applicable, of the solid organs, tissues or cells to be used in the studies. All costs required for this must be included in the application and fully justified. 2. The application must also include a 1-2 page synopsis (to be included as appendices) of the proposed treatment protocol(s) to assess safety and efficacy and incorporating the proposed mechanistic studies. Since the actual study protocols to be performed will be selected by the Steering Committee, the final protocols implemented by the Cooperative Study Group may not reflect any protocol submitted in response to this RFA. Budget requests should reflect and fully justify all costs associated with the conduct of the above studies. 3. U19 applications must include at least two proposed specific aims focused on the development, evaluation and validation of sensitive immune and/or surrogate biomarkers of the induction, maintenance, or loss of tolerance. U01 applications may include a single specific aim on the above. Proposed tolerance assay studies are to include: identification of and rationale for the immune and/or surrogate markers selected, including published data from in vitro or in vivo studies; description of and rationale for the proposed source, quantity and number of samples required; methodologies proposed to collect and analyze samples; and a discussion of how the results of the proposed studies will contribute to improvements in the capacity to utilize immune and/or surrogate biomarkers to predict the induction, maintenance or loss of tolerance. Use of new technologies, including minimally and non-invasive approaches, is encouraged. Since the actual tolerance and/or surrogate biomarker assays to be performed will be selected by the Steering Committee, the final studies carried out by the Cooperative Study Group may not reflect any single study submitted in response to this RFA. All costs required for the proposed tolerance and biomarker assays must be included in the application and must be fully justified. These include the additional costs for data collection and analyses. 4. For a U19 multi-project cooperative agreement, the application must identify the single applicant organization that will be legally and financially responsible and accountable for the use and disposition of funds awarded on the basis of this RFA to the applicant institution and other institutions participating in the consortium, if applicable, and show availability of personnel and facilities capable of performing and supporting the administrative functions necessary. Essential elements of the multi-project cooperative agreement mechanism (U19) also include: (1) a minimum of three interrelated individual research projects organized around a central theme; (2) collaborative efforts and interaction among independent projects and their investigators to achieve a common goal; (3) a single Principal Investigator who will be scientifically and administratively responsible for the group effort; (4) a single applicant institution that will be legally and financially responsible for the use and disposition of funds awarded; and (5) where necessary, support for "Core" resources or facilities, each of which shall be utilized by at least two research projects in order to facilitate the research effort. 5. The application must name a single Principal Investigator (PI) who will have scientific responsibility for the application as a whole, including all consortium-related research activities, if applicable. The PI must have substantial experience related to the scope and objectives of the RFA. In addition, applications from a consortium of institutions must designate a single investigator for each participating institution who will be responsible for on- site scientific implementation, direction and management of the studies, as well as the coordination of requirements for adjunct studies of underlying mechanisms and immune/surrogate markers. 6. The application must also demonstrate the scientific and technical expertise required to design, conduct and analyze treatment protocols, mechanistic studies and assay development and validation. 7. For a U19 multi-project cooperative agreement, the application must provide: a clear, concise plan, in narrative and diagrammatic form, that depicts the interrelationships among the research projects and the scientific and technical staff, their relevant experience/expertise, and the contribution of each to fulfillment of the objectives of this RFA; an organizational chart of the consortium showing the name, organization, and scientific discipline of the PI and of all key scientific, technical and administrative personnel; and a mechanism for selecting and replacing key professional or technical personnel. 8. If the application is from a consortium of institutions, it must provide a plan to assure the maintenance of close cooperation and effective communication among members of the consortium, including letters of commitment to this plan from all participating institutions. 9. The application must demonstrate the organization’s ability to participate effectively in cooperative, multi-center studies. The application must also include a written commitment to: participating in the cooperative study group; serving on the Steering Committee and adhering to the decisions reached by that Committee, including following the consensus treatment protocols and adjunct studies; and accepting the participation and assistance of NIH staff in accordance with the guidelines outlined under "Terms and Conditions of Award: NIH Staff Responsibilities." 10. The application must include a written commitment to design and conduct non-human primate research, in addition to the studies funded in the initial application, under circumstances in which such additional research is of significant importance to further the field of immune tolerance. Such circumstances include the evaluation of safety and efficacy and studies of underlying mechanisms for: existing tolerance induction treatment strategies in non-human primate models to produce data of critical importance to the design and conduct of scientifically sound and ethically acceptable human clinical trials; newly discovered molecular targets for the induction of immune tolerance identified through fundamental research in small animal models; and new non- human primate models of kidney transplantation, islet transplantation for type 1 diabetes, autoimmune diseases, and asthma and allergic diseases. This written commitment must also include the awardee’s willingness and agreement to: (1) prepare scientific proposals for the design, conduct and analysis of such additional studies and budget requests for all associated costs; (2) submit proposals for scientific evaluation by NIH staff and, when appropriate, non- Federal experts identified by the sponsors of this research program; and (3) accept additional funding from NIH and non-Federal organizations to support such additional investigations. The time frame within which such additional projects can be initiated and completed will be negotiated and agreed upon jointly between the awardees and the sponsors. URLs in NIH Grant Applications or Appendices All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. REVIEW CONSIDERATIONS Review Procedures Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review (CSR) and for responsiveness by NIH staff. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIH in accordance with the review criteria and minimum requirements stated above. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Council of the appropriate sponsoring institute. Review Criteria The criteria to be used in the evaluation of grant applications are listed below. To put those criteria in context, the following information is contained in instructions to the peer reviewers. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? The review criteria for U19 multi-project cooperative agreement applications are presented in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS (August 2000); this brochure is available via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm. Applicants are instructed to consult this website for details on the criteria for evaluating of each project and core as well as the overall application. Five review criteria listed above will be used to evaluate each project. Review criteria for scientific cores consist of the following: justification and usefulness to the various research projects, relationship to the central focus of the overall program, quality of relevant services or facilities, qualifications of the personnel, and appropriateness of the budget. In addition, the initial review group will examine the appropriateness of proposed project budget and duration, the provisions for the protection of animal subjects, and the safety of the research environment. Schedule Letter of Intent Receipt Date: June 11, 2001 Application Receipt Date: July 17, 2001 Scientific Review Date: October-November 2001 Advisory Council Date: February 2002 Earliest Award Date: April 1, 2002 AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merits determined by peer review, program balance, and the availability of funds. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Requests for the NIAID brochure "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS" as well as inquiries regarding programmatic (research scope and eligibility) issues, may be directed to: Shiv A. Prasad, Ph.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases 6700-B Rockledge Dr., Room 5255 Bethesda, MD 20892-7640 (20817 for express mail deliveries) Telephone: (301) 496-5598 FAX: (301) 402-2571 Email: sprasad@nih.gov Joan T. Harmon, Ph.D. Division of Diabetes, Endocrinology, and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Room 697 Bethesda, MD 20892-5640 (20817 for express mail deliveries) Telephone: 301-594-8813 FAX: 301-480-3503 Email: harmonj@ep.niddk.nih.gov Direct inquiries regarding preparation of the application and review issues, address the letter of intent to, and mail two copies of the application and all five sets of appendices to: Dr. Priti Mehrotra Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6700-B Rockledge Dr., Room 2100 Bethesda, MD 20892-7616 Use Zip Code 20817 for overnight deliveries Telephone: (301) 435-9369 FAX: (301) 402-2638 Email: pmehrotra@niaid.nih.gov Direct inquiries regarding fiscal matters to: Mollie Shea Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6700-B Rockledge Dr., Room 2247 Bethesda, MD 20892-7614 Use Zip Code 20817 for overnight deliveries Telephone: (301) 402-6576 FAX: (301) 480-3780 Email: ms256g@nih.gov Florence Danshes National Institute of Diabetes and Digestive and Kidney Diseases 2 Democracy Plaza, MSC 5456 6707 Democracy Blvd. Bethesda, MD 20892-5456 For Courier service, use Zip Code 20817 Telephone: (301) 594-8861 FAX: (301) 480-3504 Email: DANSHESF@EXTRA.NIDDK.NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Assistance No. 93.855 Immunology, Allergy, and Transplantation Research, No. 93.847 Diabetes, Endocrinology and Metabolism Research, No 93.849 Kidney Diseases, Urology and Hematology Research and No. 93.848 - Digestive Diseases and Nutrition Research. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH Grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or, in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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