Full Text AI-92-11

THE EFFECTS OF SILICONE ON THE IMMUNE RESPONSE

NIH GUIDE, Volume 21, Number 30, August 21, 1992

RFA:  AI-92-11

P.T. 34

Keywords: 
  Immunology 
  Prosthetic Devices (General) 
  Autoimmunity 


National Institute of Allergy and Infectious Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases

Letter of Intent Receipt Date:  September 15, 1992
Application Receipt Date:  November 20, 1992

PURPOSE

The Division of Allergy, Immunology and Transplantation (DAIT) of the
National Institute of Allergy and Infectious Diseases (NIAID) and the
National Institute of Arthritis and Musculoskeletal and Skin Diseases
(NIAMS) invite applications for studies focused on the short- and long-
term effects of silicone polymers and their breakdown products on the
cellular and molecular components of the immune system and its
functions and how these changes might contribute to the initiation of
self-reactivity and the induction of autoimmune disease.

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 Request
for Applications (RFA), The Effects of Silicone on the Immune Response,
is related to the priority area of diabetes and chronic disabling
conditions.  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

Applications may be submitted by public and private, foreign and
domestic, for-profit and non-profit organizations, public and private,
such as universities, colleges, hospitals, laboratories, units of State
and local governments, and eligible agencies of the Federal Government.
Women and minority investigators are encouraged to apply.  Foreign
institutions are not eligible to apply for the First Independent
Research Support and Transition (FIRST) Award.

MECHANISM OF SUPPORT

The mechanisms of support for this program will be the research project
grant (R01) and the FIRST Award (R29).  The regulations (CFR Title 42,
Part 52 and, as applicable to State and local governments, Title 45,
Part 74) and policies that govern the research grant programs of the
National Institutes of Health will prevail.  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.  The earliest anticipated award date will be July 1, 1993.

This RFA is a one-time solicitation.  Future competing continuation
applications will be considered unsolicited and compete with all
investigator-initiated applications and will be reviewed according to
the customary NIH peer review procedures.

FUNDS AVAILABLE

Up to $650,000 total costs for the first-year and additional approved
expenses for up to five years, has been committed to fund applications
submitted in response to this RFA.  The NIAID and the NIAMS plan to
make approximately three and one awards, respectively in FY 1993,
contingent on the receipt of highly meritorious applications.  Funding
beyond the first and subsequent years of the grant will be contingent
upon satisfactory progress during the preceding years and the
availability of funds.

RESEARCH OBJECTIVES

Background

Silicone-containing implants and silicone injections have been linked
to the development of autoimmune-like diseases, such as scleroderma,
arthritis, and dermatomyositis, in some patients.  However, there are
no solid scientific data to support or rule out the link between the
onset of autoimmune disease and the presence of silicone in intact or
leaky implants.  Furthermore, very limited information is available
regarding the effects of silicone administration on the development of
normal immune responses and the maintenance of self-tolerance.  From
the available preliminary information, it appears that some silicone
polymers (e.g., D4) have biological activity in vivo similar to
Freund's complete adjuvant.  Basic research on the effects of silicone
in the immune system will be valuable in determining the safety of
these devices.

Research Goals and Scope

Some examples of relevant research topics include, but are not limited
to:

o  Effects of short- and long-term administration of silicone on the
production, structure, and function of lymphocytes

o  Effects of intracellular accumulation of silicone and low molecular
weight derivatives in macrophage function, including antigen processing
and presentation, cytokine production, and cytotoxic activities

o  Characterization of the profiles and fine specificity of
autoantibodies obtained from the sera of patients developing
autoimmune-like syndromes who have also received implants

o  Evaluation of the effects of silicone on lymphocyte and monocyte
interactions with endothelial cells and fibroblasts and the production
and function of adhesion molecules

o  Analysis of silicone effects on the evolution of autoimmune disease
in experimental systems, with regard to disease induction, course, and
immunologic parameters.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDIES

NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements are required to include
minorities and women in study populations so that research findings can
be of benefit to all persons at risk of the disease, disorder or
condition under study; special emphasis should be placed on the need
for inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research design
and sample size appropriate for the scientific objectives of the study.
This information must be included in the form PHS 398 in Sections 1-4
of the Research Plan and summarized in Section 5, Human Subjects.
Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However, NIH
recognizes that it may not be feasible or appropriate in all research
projects to include representation of the full array of U.S.
racial/ethnic minority populations (i.e., Native Americans, including
American Indians or Alaskan Natives, Asian/Pacific Islanders, Blacks,
and Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention, diagnosis, or treatment of diseases, disorders or
conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the U.S. populations, including minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and will be reflected in
assigning the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.

LETTER OF INTENT

Prospective applicants are asked to submit by September 15, 1992, a
letter of intent that includes a descriptive title of the overall
proposed research, the name and institution of the Principal
Investigator, and a list of the names of key investigators and their
institution(s).  The letter of intent is requested in order to provide
an indication of the number and scope of applications to be reviewed to
allow early preparations for review.  The letter of intent is not
binding and does not commit the sender to submit an application, nor is
it a requirement for submission of an application.  The letter of
intent is to be directed to:

Susana A. Serrate-Sztein, M.D.
Chief, Autoimmunity Section
Clinical Immunology Branch
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A20
Bethesda, MD  20892
Telephone:  (301) 496-7985

APPLICATION PROCEDURES

Applications are to be submitted on the research grant application form
PHS 398 (rev. 9/91).  For purposes of identification and processing,
the box "Yes" should be marked in item 2a on the face page of the
application; the RFA number and the words "The Effects of Silicone on
the Immune Response" must be entered.

These application forms are available in most institutional business
offices and may be obtained from the Office of Grants Inquiries,
Division of Research Grants, National Institutes of Health, 5333
Westbard Avenue, Room 449, Bethesda, MD 20892, telephone (301)
496-7441.

The receipt date for applications is November 20, 1992.  Applications
that are not received by November 20, 1992, or that do not conform to
the instructions contained in the PHS 398 (rev. 9/91) application kit,
will be returned to the applicant without review.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed, exact, single-sided photocopies, in one
package to:

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

In addition, mail two exact copies of the application directly to Dr.
Serrate-Sztein at the address given above under LETTER OF INTENT.

The RFA label available in the application form PHS 398 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.

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 must be included with the
application.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by the Division of Research
Grants (DRG) for completeness and by NIAID and NIAMS staff for
responsiveness.  Applications for the FIRST Award (R29) must include at
least three sealed letters of reference attached to the face page of
the original application.  FIRST Award (R29) applications submitted
without the required number of reference letters will be considered
incomplete and returned without review.  Those judged to be incomplete
and/or non-responsive will be returned to the applicant without review.
Applications will be reviewed for scientific and technical merit by an
appropriate scientific peer review group convened by the DRG, NIH.

The second level of review will be provided by the National Advisory
Allergy and Infectious Diseases Council or the National Arthritis and
Musculoskeletal Diseases Council in May 1993.

Applications in response to this solicitation will be reviewed by the
usual NIH peer review procedures.  The factors to be considered in the
evaluation of scientific merit of each application will be those used
in the review of unsolicited research project grant applications,
including the novelty, originality, and feasibility of the approach;
the training, experience, and research competence of the
investigator(s); the adequacy of the experimental design; the adequacy
and suitability of the facilities; the appropriateness of the requested
budget to the work proposed; and the adherence, whenever appropriate,
to NIH guidelines concerning adequate representation of minorities and
women in clinical research.

AWARD CRITERIA

The earliest anticipated date of award is July 1, 1993.  The following
will be considered in making funding decisions:  quality of the
proposed project as determined by peer review and 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.

Direct inquiries regarding programmatic issues to:

Susana Serrate-Sztein, M.D.
Chief, Autoimmunity Section
Clinical Immunology Branch
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A20
Bethesda, MD  20892
Telephone:  (301) 496-7985
FAX:  (301) 402-2571

Dr. Michael D. Lockshin
Director, Extramural Programs
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Building 31, Room 4C32
Bethesda, MD  20892
Telephone:  (301) 496-0802

Direct inquiries regarding fiscal and administrative matters to:

Mr. Jeffrey Carow
Chief, Immunology Grants Management Section
Grants Management Branch
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B29
Bethesda, MD  20892
Telephone:  (301) 496-7075

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.855 - Allergy, Immunology and Transplantation
Research and No. 93.846 - Arhtritis and Musculoskeletal and Skin
Diseases Research.  Grants are awarded under the authority of the
Public Health Service Act, Section 301 (42 USC 241) and administered
under PHS grants policies and Federal Regulations, most specifically at
42 CFR Part 52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

.

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