Full Text AI-94-023

THE MECHANISMS OF EMBRYONIC/FETAL-MATERNAL TOLERANCE

NIH GUIDE, Volume 23, Number 24, June 24, 1994

RFA:  AI-94-023

P.T. 34

Keywords: 
  0705048 
  Human Reproduction/Fertility 
  Pregnancy 
  Immunogenetics 


National Institute of Allergy and Infectious Diseases
National Institute of Child Health and Human Development
Office of Research on Women's Health

Letter of Intent Receipt Date:  August 15, 1994
Application Receipt Date:  November 16, 1994

PURPOSE

The Division of Allergy, Immunology, and Transplantation of the
National Institute of Allergy and Infectious Diseases (NIAID); the
Developmental Biology, Genetics, and Teratology Branch, the Center for
Research for Mothers and Children, and the Reproductive Sciences
Branch, Center for Population Research of the National Institute of
Child Health and Human Development (NICHD); and the Office of Research
on Women's Health (ORWH) of the Office of the NIH Director invite
applications for basic studies designed to identify the underlying
immunologic and/or genetic mechanism(s) that protect the embryo and
fetus from maternal rejection and to elucidate the interactions of the
fetal and maternal immune systems in successful pregnancy.  Despite
genetic differences known to elicit strong immunologic responses under
other circumstances, i.e., Major Histocompatibility Complex (MHC)
disparities, mothers do not reject their semiallogeneic embryos or
fetuses.  This remarkable immunologic accommodation is undoubtedly due
to many finely orchestrated events.  The goal of this initiative is to
promote research that will advance our understanding of the underlying
mechanisms of this unique form of immunologic tolerance and lead to
improved clinical applications.

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 Mechanisms of Embryonic/Fetal-Maternal
Tolerance, is related to the priority areas of immunization and
infectious diseases, family planning, and maternal and infant health.
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 domestic and foreign, for-profit and
non-profit organizations, public and private institutions, such as
universities, colleges, hospitals, laboratories, units of State or
local governments, and eligible agencies of the Federal government.
Foreign institutions are not eligible to apply for First Independent
Research Support and Transition (FIRST) (R29) Awards.  Applications
from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

The mechanisms of support will be the individual research project grant
(R01) and the FIRST (R29) award.  Multidisciplinary approaches that
involve collaborative efforts among investigators in the fields of
basic immunology, molecular biology, cell biology, biochemistry, and
genetics are strongly encouraged.  The total project period for an
application submitted in response to this RFA may not exceed five
years; a foreign application may not request more than three years of
support.

This RFA is a one-time solicitation.  Future competing renewal
applications will compete with all investigator-initiated applications
and will be managed according to customary referral and review
procedures.

FUNDS AVAILABLE

The estimated funds available for the total (direct and indirect)
first-year costs of all awards made under this RFA will be $2,000,000.
In Fiscal Year 1995, the NIAID and the ORWH plan to provide up to
$1,000,000 to fund up to five R01 and/or R29s and the NICHD plans to
provide up to $1,000,000 to fund up to six R01s and/or R29s.  PHS
policies governing grants administration and management will apply.
This level of support is dependent on the receipt of a sufficient
number of applications of high scientific merit.  Although this program
is provided for in the financial plans of the NIAID, the NICHD, and the
ORWH, 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

Pregnancy, which is experienced by over six million women per year in
the United States, is an outstanding example of immune accommodation to
immunologically incompatible tissue (embryonic/fetal).  The operative
mechanisms that permit the embryo and/or fetus to develop without being
rejected, if identified, could provide insights into the induction,
maintenance, and control of immunologic tolerance.

Evidence suggests that protection of the embryo or fetus from maternal
immunological rejection is multifactorial, possibly involving modulated
or unique MHC/HLA expression, hormonal changes during pregnancy, unique
expression of non-MHC cell surface molecules, and the specific function
of cells and cytokines at the uteroplacental interface.  For example,
recent studies of the expression of the unique, nonpolymorphic HLA-G
class I MHC molecule expressed primarily on extravillous trophoblast
cells strongly implicate a role for the HLA system in fetal tolerance.
Differential expression and/or repression of classical HLA class I
molecules on embryonic or fetal tissue seems required for the
maintenance of pregnancy and the regulatory molecular mechanisms are
now being studied.  Other cell surface molecules, such as complement
regulatory proteins, may also be critical for embryonic and/or fetal
survival.

Although cells at the uteroplacental interface have been identified,
the interactions of these cells, their products (cytokines) and
receptors, and the roles they play in the protection of the embryo and
fetus from maternal rejection remain incompletely described.  Recent
studies suggest unique control mechanisms exist that may, in part,
ensure a tolerant environment, e.g., placental macrophages were found
to have altered antigen processing function.

Much interest has focussed on cytokines identified as important in
establishing, maintaining, and regulating pregnancy, i.e., TGF-beta,
TNF, IL-6, LIF, CSF-1, GM-CSF and IFN-gamma.  Elucidating their
regulation, expression in nonlymphoid tissue, and receptor biology, as
well as the identification of other relevant receptor-ligand (cytokine)
interactions that contribute to embryonic and fetal tolerance, is
essential for a comprehensive understanding of this event.

Understanding the basic mechanisms of embryonic/fetal-maternal
tolerance has considerable potential for clinical application, e.g.,
controlling the transmission of infectious maternal disease to the
fetus, devising and improving therapies for infertility, and
identifying and preventing dysregulations that result in unsuccessful
pregnancy.

Research Objectives and Scope

The objective of this RFA is to support innovative research designed to
apply current research technologies and scientific advances to
facilitate the identification of mechanisms that protect the embryo and
fetus from maternal immunologic rejection as well as the elucidation of
embryonic/fetal-maternal immune interactions.  Suitable models of study
may include in vitro and in vivo animal models, transgenic animal
models, and human studies (preclinical or clinical).

Relevant topics of research include, but are not limited to, the
following:

o  The role of MHC in embryonic/fetal-maternal tolerance, including:

-  identification of regulatory mechanisms (transcription,  translation
and post-translational modifications) of MHC genes and functional
expression, lack of expression, or repression on embryonic/fetal
tissues as they relate to immune function;

-  differential MHC expression and the kinetics of this expression; and

-  identification of unique MHC molecule(s) involved in embryonic/fetal
accommodation and elucidation of the mechanisms of this accommodation.

o  Studies of the expression and function of unique cell surface
molecules (non-MHC molecules) that may play a role in embryonic/fetal
protection.

o  The gene regulation and differential expression of cytokines and
their receptors (soluble or membrane-bound) and the role this
expression has on embryonic/fetal tolerance and successful pregnancy.

o  The role of immune cells in embryonic/fetal maternal tolerance,
including:

-  identification of immune cell populations that have a regulatory
role in embryonic/fetal tolerance and characterization of their
effector function(s); and

-  delineation of the function(s) of immune cells found in the pregnant
uterus and/or placenta which ensures a tolerant environment, e.g.,
altered antigen-processing/presentation ability of antigen presenting
cells.

o  Interaction of the endocrine and immune system as it pertains to the
induction and maintenance of embryonic/fetal-maternal tolerance.

NOTE:  Studies may address any post-fertilization influencing
immunologic events.  Studies of infectious disease as it relates to the
regulation - or dysregulation - of embryonic/fetal- maternal tolerance
are within the scope of this RFA with the exception of sexually
transmitted diseases (STDs) and the Human Immunodeficiency Virus (HIV).
In addition, development of treatments for infertility or miscarriages;
and contraception development are not within the scope of this RFA.

STUDY POPULATIONS

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 subpopulations 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 new 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 has been published in the Federal
Register of March 28, 1994 (FR 59 14508-14513), and reprinted in the
NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number
11.

Investigators may obtain copies from these sources or from the program
staff or contact person listed below.  Program staff may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by August 15, 1994, 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 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 avoid conflict
of interest in the review.  The letter of intent is to be sent to Dr.
Allan Lock at the address listed under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the research grant application form
PHS 398 (rev. 09/91).  For purposes of identification and processing,
item 2a on the face page of the application must be marked "YES" and
the RFA number and the words "THE MECHANISMS OF
EMBRYONIC/FETAL-MATERNAL TOLERANCE" must be typed in.

These application forms may be obtained from the institution's office
for sponsored research or its equivalent and from the Office of Grants
Information, Division of Research Grants, National Institutes of
Health, 5333 Westbard Avenue, Room 449, Bethesda, Maryland 20892,
telephone (301) 435-0714.

It is highly recommended that the appropriate NIAID or NICHD program
contact be consulted before submitting the letter of intent and during
the early stages of preparation of the application.  (See program
contacts in INQUIRIES below.)

Applications must be received by November 16, 1994.

Applications that do not conform to the instructions contained in PHS
398 (rev. 09/91) application kit, will be judged nonresponsive and will
be returned to the applicant.

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.  FIRST award (R29) applications
must include at least three sealed letters of reference attached to the
face page of the original application.  FIRST applications submitted
without the required number of reference letters will be considered
incomplete and will be returned without review.

Applications received after the receipt date will be returned without
review.  The Division of Research Grants (DRG) will not accept any
application in response to this RFA that is essentially the same as one
currently pending initial review, unless the applicant withdraws the
pending application.  This does not exclude the submission of
substantial revisions of an application already reviewed.  These
applications must, however, include an introduction addressing the
previous critique.

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**

At the time of submission, two additional exact copies of the grant
application and all five sets of the appendix must also be sent to Dr.
Olivia Preble at the address listed under INQUIRIES.

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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the NIH
Division of Research Grants (DRG) and for responsiveness by NIAID and
NICHD staff.  Incomplete applications will be returned to the applicant
without further consideration.  If NIAID or NICHD staff find that the
application is not responsive to the RFA, it will be returned 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 and the NICHD 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 promptly notified.  The second level of review
will be provided by the National Advisory Allergy and Infectious
Diseases Council and/or the National Advisory Child Health and Human
Development Council.

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;
and the adherence to NIH guidelines concerning adequate representation
of women and minorities in clinical research.

While the following review factors do not usually influence the
priority score, they are nonetheless carefully considered by the
initial review group: the appropriateness of the requested budget to
the work proposed; and the adequacy of protection of human subjects
and/or animals in research.  Any documented concerns expressed by the
initial review group about any of these factors on a given application
may influence the recommendation of the Advisory Council concerning
funding of that application.

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.

Direct inquiries regarding programmatic issues and address the letter
of intent to:

M. Michele Hogan, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A21
6003 Executive Boulevard
Bethesda, MD  20892
Telephone: (301) 496-7551
FAX:  (301) 402-2571

Allan Lock, D.V.M.
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
Building 61E, Room 4B01
6100 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-5541
FAX:  (301) 402-4083

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

Olivia T. Preble, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C20
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8208
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Ms. Cynthia R. McDermott
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B22
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7075

Mr. E. Douglas Shawver
Office of Grants and Contracts
National Institute of Child Health and Human Development
Building 61E, Room 8A17K
6100 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-1303

Schedule

Letter of Intent Receipt Date:  August 15, 1994
Application Receipt Date:       November 16, 1994
Scientific Review Date:         February 1995
Advisory Council Date:          June 1995
Earliest Award Date:            August 1995

AUTHORITY AND REGULATIONS

The NIAID program is described in the Catalog of Federal Domestic
Assistance, No. 93.855 - Immunology, Allergy and Transplantation
Research; and the NICHD program in No. 93.864 - Population Research and
No. 93.865 - Research for Mothers and Children. Awards for NIAID will
be made under the authority of the Public Health Service Act, Title
III, Section 301 (Public Law 78-410, as amended; 42 USC 241) and
administered under PHS grants policies and Federal Regulations 45 CFR
Part 74 and 92.  Awards for NICHD are made under the authorization 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 CFR
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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