Full Text AI-95-009

IMMUNOPATHOGENESIS OF CHRONIC GRAFT REJECTION

NIH GUIDE, Volume 24, Number 3, January 27, 1995

RFA:  AI-95-009

P.T. 34

Keywords: 
  Pathogenesis 
  Immunology 
  Immunosuppression 
  Transplantation of Organs 
  Biology, Cellular 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  July 1, 1995
Application Receipt Date:  October 17, 1995

APPLICATIONS IN RESPONSE TO THIS REQUEST FOR APPLICATIONS (RFA) MUST
BE PREPARED USING A MODIFIED (ABBREVIATED) GRANT APPLICATION FORMAT;
SPECIFIC INSTRUCTIONS FOR COMPLETING THE APPLICATION ARE IN A
BROCHURE ENTITLED "INSTRUCTIONS FOR ABBREVIATED APPLICATIONS FOR
PROGRAM PROJECT (P01) GRANTS IN RESPONSE TO RFA AI-95-009,
IMMUNOPATHOGENESIS OF CHRONIC GRAFT REJECTION" AVAILABLE FROM NIAID
STAFF IDENTIFIED UNDER INQUIRIES.

PURPOSE

The Division of Allergy, Immunology and Transplantation of the
National Institute of Allergy and Infectious Diseases (NIAID),
National Institutes of Health (NIH), invites applications for program
projects in the immunopathogenesis of chronic graft rejection to
evaluate the immune response to organ allografts, to elucidate the
important cellular and molecular events of both the induction and
effector phases of chronic solid organ graft rejection, and to
develop improved therapeutic approaches to enhance long-term graft
survival.  Collaboration between basic scientists and clinical
investigators is encouraged.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Immunopathogenesis of Chronic Graft Rejection, is related to the
priority area of clinical prevention services.  Potential applicants
may obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-782-3238).

ELIGIBILITY REQUIREMENTS

Research grant 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 organizations 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 mechanism of support will be the program project (P01) grant.
This mechanism supports broadly based multidisciplinary research
programs that have a well-defined central research focus or
objective.  An important feature of the program project is that the
interrelationships of the individual scientifically meritorious
projects will result in a greater contribution to the overall program
goals than if each project were pursued individually.  The program
project grant consists of a minimum of three interrelated individual
research projects that contribute to the program objective.  The
program project grant also can provide support for certain common
resources termed cores.  Such resources should be utilized by two or
more projects within the program project.

Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  The total
project period may not exceed five years.  At this time, the NIAID is
administratively limiting the duration of P01 grants to four years;
this administrative limitation may change in the future.  The
earliest anticipated award date is August 1996.

FUNDS AVAILABLE

The estimated total funds (direct and indirect) available for the
first year of support for this RFA will be $1.5 million.  In fiscal
year 1996, the NIAID plans to fund approximately two program projects
related to this RFA.  This level of support is dependent on the
receipt of a sufficient number of applications of high scientific
merit.  Applications may not request budgets in excess of $750,000 in
total (direct and indirect) costs in the first year.  NIH is
currently limiting annual inflationary increases to no more than four
percent for future years.  The usual PHS policies governing grants
administration and management will apply.  Although this program is
provided for in the financial plans of the NIAID, 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.  At this time, the NIAID has not
determined whether or how this solicitation will be continued beyond
the present RFA.

RESEARCH OBJECTIVES

Applications in response to this RFA must be prepared using a
modified (abbreviated) grant application format; specific
instructions for completing the application are in the special
brochure (see INQUIRIES below).

Background

Immunosuppressive agents and therapeutic approaches developed in the
last decade have significantly improved short-term graft survival.
However, long-term graft survival remains poor, with 50 to 90 percent
percent of all grafts failing within five years depending on what
organ is transplanted.  An improved understanding of the factors
responsible for chronic rejection is critical to advancing effective
therapeutic regimens.  Among the gaps in our current knowledge are:
factors determining the onset and severity; targets of immune
reactivity; and control or regulation of the process of chronic
rejection.  These gaps have hindered the development of effective and
safe treatments.  Overcoming chronic rejection is important to
increasing graft and patient survival and quality of life for
transplant recipients and reducing the need for retransplantation
which directly affects the supply of donor organs.  Therefore,
overcoming chronic rejection will consequently reduce health care
costs.

Research Objectives and Scope

The research objective of this RFA is to support basic and clinical
research on the immunopathogenesis of chronic solid organ graft
rejection which will, in turn, lead to improved methods of diagnosis
and treatment.  The fact that chronic rejection exists in the face of
the aggressive immunosuppression routinely administered to every
transplant recipient illustrates the ineffectiveness of current
therapeutic approaches.

The recent literature on chronic rejection is primarily descriptive
and our understanding of chronic rejection remains poor in several
areas, including:  the basic immunobiology of chronic rejection;
diagnostic criteria and timing of diagnostic tests; and methods to
prevent or reverse this process.  Among the unresolved issues are:
what are the cell types (TH1 vs. TH2) responsible for chronic
rejection; what cytokines do they elaborate and what is their
specificity; what can explain the presence of graft infiltrating T
cells in transplanted organs without chronic rejection; what role, if
any, do antibodies play in chronic rejection and what is the
contribution of antibody-dependant-cell-cytotoxicity (ADCC) to
chronic rejection?

Criteria for the diagnosis of chronic rejection also need
clarification.  At present, diagnosis is made on the basis of loss of
organ function combined with tissue biopsy.  Ideally, it would be
preferable to develop the knowledge and capability to diagnose
chronic rejection prior to the loss of organ function.  Further
delineation of the immune parameters that are diagnostic of the onset
of chronic rejection are needed to allow earlier diagnosis and
intervention.  Similarly, the successful reversal of ongoing chronic
rejection will rely on understanding the basic processes of chronic
rejection and may require new therapeutic agents or regimens.

Applications should emphasize:  collaborative research between basic
scientists and clinical investigators; the use of new and innovative
approaches to enhance understanding of the immunopathogenesis of
chronic rejection and the clinical application and relevance of such
approaches; and the use of the most up-to-date concepts and
techniques of immunology.  The inclusion of basic research and
preclinical studies using laboratory animals is encouraged.  However,
animal models must be applicable to the treatment and/or prevention
of human chronic graft rejection and the studies proposed must be
directly relevant to understanding the underlying basic mechanisms of
chronic rejection.

Examples of studies relevant to this RFA include, but are not limited
to, the following:

o  Identification of the targets of the immune response in chronic
rejection.  Are the antigens being recognized by the effector cells
of chronic rejection identical to those being recognized in acute
rejection?  If not, what are the differences and how are they
recognized?  What are the relative contributions of T and B cells to
the process of chronic rejection?

o  Further delineation of the molecular process of chronic rejection,
including studies on cytokines or infiltrating cell types, initiating
as well as mediators, and methods to attenuate the actions of these
cells.

o  Development of new and innovative therapeutic approaches for the
treatment and/or prevention of chronic rejection.

o  Development of new and innovative approaches or improvement of
existing approaches to the earlier detection of chronic rejection.
For example, would routine biopsies at regular intervals enhance
predictive capability?  What approaches could distinguish between
clinically relevant pathologic changes (e.g., interstitial
inflammation, fibrosis, vascular intimal hyperplasia) associated with
acute vs. chronic rejection?  What are the important components and
the potential effectiveness of using a standardized, post-transplant
assessment approach for the earlier detection of chronic rejection?

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority groups
and their sub-populations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990.  The new policy contains some
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and printed in
the NIH Guide for Grants and Contracts, Volume 23, Number 11, March
18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by July 1, 1995, a letter
of intent that includes a descriptive title of the overall proposed
research, the name, address, and telephone number of the Principal
Investigator, a list of the key investigators and their
institution(s), 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
NIAID staff to estimate the potential review workload and to avoid
conflict of interest in the review.

The letter of intent is to be sent to Dr. Justina Schwemberger at the
address
listed under INQUIRIES.

APPLICATION PROCEDURES

NOTE:  SEE BROCHURE FOR SPECIAL INSTRUCTIONS FOR COMPLETION OF GRANT
APPLICATIONS IN RESPONSE TO THIS RFA.

Applications are to be submitted on form PHS 398 (rev. 9/91), the
standard application form for research grants.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, Westwood Building,
Room 449, Bethesda, MD 20892, telephone 301/710-0267.  Applicants
must adhere to the format and requirements specified in the PHS 398
application kit.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or principal investigator could be included
with the application.

For purposes of identification and processing, mark "YES" in item 2a
on the face page of the application and type in the RFA number,
AI-95-009, and the title "IMMUNOPATHOGENESIS OF CHRONIC GRAFT
REJECTION."  The RFA label available in the form PHS 398 must be
affixed to the bottom of the face page of the original application.
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 signed, typewritten original of the application, including the
Checklist, and three exact single-sided copies must be sent to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies and all five sets of
appendices must also be sent to Dr. Justina Schwemberger at the
address listed under INQUIRIES.

To ensure their review, applications must be received by both the
Division of Research Grants and Dr. Justina Schwemberger by October
17, 1995. Applications not received by October 17, 1995 will be
considered non-responsive and will be returned to the applicant
without review.

Concurrent submission of an R01 and a Component Project of a
Multi-project Application:

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.

Special Instructions for Completion of Applications in Response to
This RFA

The NIH has recently been designated a "reinvention laboratory" by
the Public Health Service.  One NIH reinvention objective is to
simplify and improve each stage in the grant process:  application,
review, award, and administration

Experiments are being conducted to determine how to reduce the
administrative burden in applying for an NIH grant without
compromising the information needed by the initial scientific peer
review group to assess the scientific merit of the application and
the reasonableness of the proposed budget.

The brochure, Instructions for Abbreviated Applications for Program
Project (P01) Grants in Response to RFA-AI-95-009, Immunopathogenesis
of Chronic Graft Rejection, presents specific instructions for
sections of the PHS 398 (rev. 9/91) application form, which should be
completed differently than usual.  Some sections in the application
are modified and others should not be completed for submission of the
application, but will be requested if the application receives a
score in the fundable range.  For all other items in the application,
follow the usual instructions on pages 9-32 of the PHS 398 booklet.

REVIEW CONSIDERATIONS

Review Procedures

Upon receipt, applications will be reviewed for completeness by the
NIH Division of Research Grants (DRG) and for responsiveness by NIAID
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 NIAID in accordance with the review
criteria stated below.  As part of the initial merit review, a
process (triage) may be used by the initial review group in which
applications will be determined to be competitive or non-competitive
based on their scientific merit relative to other applications
received in response to the RFA.  Applications judged to be
competitive will be discussed and be assigned a priority score.
Applications determined to be non-competitive will be withdrawn from
further consideration and the Principal Investigator and the official
signing for the applicant organization will be notified.  The second
level of review will be provided by the National Advisory Allergy and
Infectious Diseases Council.

Review Criteria

The review criteria for P01 grant applications in response to this
RFA are presented in the special brochure.  The program project grant
application should include a justification for the appropriateness of
that granting mechanism for the proposed project.  The distinguishing
features of a program project grant include:

o  A well-defined, unifying goal or problem area of research to which
each project relates and contributes, thereby producing a research
environment that allows each research effort to share the creative
strengths of others.

o  A program director who possesses recognized scientific and
administrative competence.  He/she must demonstrate a substantial
commitment to the program in time and effort thereby exercising
leadership in providing overall direction and in upholding rigorous
scientific conduct.

o  Each research project must, as assessed by peer review, stand on
its own independent scientific merit, as well as complement other
projects whenever feasible.

o  The projects require the participation of established
investigators in several disciplines or investigators with special
expertise in several areas of one discipline.  All investigators must
contribute to and share the responsibilities of fulfilling the
program objective.

o  Ability of the proposed research to provide both basic
immunological knowledge and clinically relevant interventions that
will result in improvement in the methods to control solid organ
chronic rejection.  The appropriateness of the proposed experimental
plan to validate the utility of the chosen strategy will be
considered in this regard.

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review, program priorities, 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 brochure "Instructions for Abbreviated Applications
for Program Project (P01) Grants in Response to RFA AI-95-009,
Immunopathogenesis of Chronic Graft Rejection," as well as inquiries
regarding programmatic issues, may be directed to:

Stephen M. Rose, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A14
6003 Executive Boulevard
Bethesda, MD  20892-7640
Telephone:  (301) 496-5598
FAX:  (301) 402-2571
Email:  sr8j@nih.gov

Direct inquiries regarding review issues, address the letter of
intent to, and mail two copies of the application and all five sets
of appendices to:

Justina S. Schwemberger, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C14
6003 Executive Boulevard
Bethesda, MD  20892-7610
Telephone:  (301) 496-9977
FAX:  (301) 402-2638
Email:  js74g@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Barbara Huffman
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C26
6003 Executive Boulevard
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
Email:  bh23q@nih.gov

Direct inquiries regarding the special instructions for preparation
of the grant application to:

John J. McGowan, Ph.D.
Director, Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3C20
6003 Executive Boulevard
Bethesda, MD  20892-7610
Telephone:  (301) 496-7291
FAX:  (301) 402-0369
Email:  ac20a@nih.gov

Schedule

Letter of Intent Receipt Date:  July 1, 1995
Application Receipt Date:       October 17, 1995
Scientific Review Date:         February 1996
Advisory Council Date:          May 1996
Earliest Date of Award:         August 1996

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.855 - Immunology, Allergy, and Transplantation
Research.  Awards will be made under the authority of the Public
Health Service Act, Title IV, Part A, (Public Law 78-410, as amended
by Public Law 99-158, 42 USC 241 and 285) and administered under PHS
grants policies and Federal Regulations 42 CFR 52 and 45 CRF Part 74.
This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency
review.

The Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free work place and promote the nonuse
of all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American
people.

.

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