Full Text PA-97-081
NIH GUIDE, Volume 26, Number 24, July 25, 1997
PA NUMBER:  PA-97-081
P.T. 34

  Clinical Medicine, General 

National Institutes of Health
The National Institutes of Health (NIH) invites applications that
will elucidate basic mechanisms responsible for inducing and
maintaining antigen-specific immune tolerance, that will facilitate
translation of experimental knowledge on immune tolerance into
clinical therapies for the treatment or prevention of immune-mediated
disease, or that will promote more effective development of vaccines
by preventing
pathogen-induced immune tolerance.
Each NIH PA addresses one or more of 22 Health Promotion and Disease
Prevention priority areas identified.  These areas can be found via
the WWW at URL:  http://www.crisny.org/health/us/health7.html
Applications may be submitted by 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. Domestic and foreign
institutions are eligible to apply for R01 grants. Foreign
institutions are not eligible for First Independent Research Support
and Transition(FIRST)awards(R29). Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as
Principal Investigators.
Traditional research project grant (R01)and FIRST(R29) applications
may be submitted in response to this announcement.  Applications for
R01 grants may request up to five (5) years of support; applications
for R29 grants must request five years of support.
Responsibility for the planning, direction, and execution of the
proposed research for all applicable mechanisms of support will be
solely that of the applicant.
The immune system is uniquely characterized by its highly diverse and
clonally expressed repertoire of lymphocyte receptors that can
recognize a very broad spectrum of both foreign and self antigens.
Those cells with receptors for self antigens are eliminated, or
tolerized, in healthy individuals by a variety of active mechanisms
to prevent pathogenic autoimmunity. Autoreactive cells may be
physically deleted by the induction of apoptosis after self-antigen
recognition, may become anergic without deletion, or may be
functionally inhibited by regulatory cytokines or cells. These same
mechanisms operate during the induction of tolerance to foreign
antigens and may be exploited to inactivate specific, detrimental
immune responses without compromising the ability to respond to the
remaining universe of pathogens, because tolerance is induced only in
those lymphocytes that recognize the offending antigens. Although
much has been learned in recent years about the molecular events that
distinguish tolerogenic from immunogenic signals, it is still
difficult to predict the outcome of antigenic exposure in vivo, and
further elucidation of tolerance mechanisms is needed at the basic
It is important to define the molecular mechanisms that determine
whether antigen recognition results in anergy or apoptosis rather
than effector or memory cell generation, and to identify genetic
factors that regulate these mechanisms. Basic studies on the
influence of cytokines on tolerance induction and maintenance, and on
the importance of antigen dose, affinity and site of entry are also
Immune tolerance is highly relevant to a wide range of clinically
important applications. Antigen-specific tolerance induction is a
major goal for the treatment or prevention of autoimmune disease and
graft rejection, which are currently controlled by nonspecific,
immunosuppressive therapies that result in increased rates of
infections, cancers and drug-related pathology. Other applications
include allergies and asthma, bone marrow replacement and future gene
therapy for a large number of human diseases. A greater understanding
of tolerogenic processes is also needed to enhance vaccine
development, in order to prevent pathogen-induced tolerance during
Very productive basic research in immunology and other fields of
study has provided unprecedented opportunities for clinical
breakthroughs in this area, due to identification of relevant
molecular pathways, new technologies, new reagents and animal model
development for in vivo studies. Although work is still needed at the
basic level to obtain a more detailed understanding of tolerance vs
immunity, the application of existing knowledge to clinical
situations has already begun, and an expanded investment in pre-
clinical and clinical research is clearly warranted. At present, many
clinical studies are conducted by industry to determine efficacy with
little emphasis on defining the mechanisms involved. However,
enhanced understanding of the mechanisms of immune response vs
tolerance in the clinical setting should allow more appropriate
selection of therapeutic agents as well as improved results and more
predictable outcomes.
Research Objectives and Scope
Multidisciplinary research focused on the understanding and/or
modulation of antigen-specific immune tolerance mechanisms is sought.
Both basic and clinical research projects are encouraged, but
clinical trials will not be supported on this PA. Specific examples
of research areas of interest include, but are not limited to:
o Specific immune tolerance mechanisms in human lymphocytes, and
novel experimental approaches to define such mechanisms;
o Development and validation of clinically relevant animal models of
immune tolerance, including transplantation, autoimmune or infectious
pathogen systems, in order to define mechanisms of tolerance
induction and maintenance, degree of efficacy and potential adverse
o Animal models to study tolerance to transplanted allogeneic or
xenogeneic lymphoid tissues for application to immune replacement in
HIV disease;
o Analysis of the genes and biochemical pathways involved in the
induction and long-term maintenance of immune tolerance, and
molecular pathways by which tolerance is prevented or reversed;
o Loss of self-tolerance due to antigen crossreaction during
infection or vaccination;
o Induction of tolerance by microbial products such as antagonistic
peptides or superantigens, or by pathogen-induced, host-derived
immunosuppressive factors;
o Development of technologies to study tolerance vs immunity at the
single cell level to identify mechanisms or immune markers in vivo;
o Tolerance induction at mucosal surfaces and the prevention of
tolerance to oral vaccines;
o Tolerogenic approaches for the primary prevention of asthma and the
treatment of allergies;
o Definition of tolerance mechanisms in immune-privileged sites, such
as the central nervous system, the eye and the maternal-fetal
o Analysis of tolerance induction in neonates and in aged
o Effects of chronic maternal infections on immune responses in their
progeny; and
o Protocols to induce vector-specific tolerance prior to vector-
mediated vaccine delivery or gene therapy.
See NIH Guide of March 18, 1994 for requirements for inclusion of
Women and Minorities in research.  It is available via the WWW at
URL: http://www.nih.gov/grants (select NIH Guide for Grants and
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted on the standard application
deadlines as indicated on the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Office of Extramural Outreach and Information,
National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone (301) 710-0267, email:
For purposes of identification and processing, item 2 on the face
page of the application must be marked "YES".  The PA number and the
also be typed in section 2.
The completed, signed original and five legible, single-sided copies
of the application must be sent or delivered to:
BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)
R29 applications must include at least three (3) 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
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 Center as a resource for
conducting the proposed research.  If so, a letter of agreement from
the GCRC Program Director must be included in the application
Review Procedures
Applications will be assigned on the basis of established PHS
referral guidelines. Upon receipt, applications will be reviewed for
completeness by the NIH Division of Research Grants.  Incomplete
applications will be returned to the applicant without further
Applications will be reviewed for scientific and technical merit by
study sections of the Division of Research Grants, NIH, in accordance
with the standard NIH peer review procedures. 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 the applications
under review, will be discussed, assigned a priority score, and
receive a second level review by the appropriate national advisory
Review Criteria
The five criteria to be used in the evaluation of grant applications
are listed below.
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
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 initial review group will also examine: the appropriateness of
proposed project budget and duration; the adequacy of plans to
include both genders and minorities and their subgroups as
appropriate for the scientific goals of the research and plans for
the recruitment and retention of subjects; the provisions for the
protection of human and animal subjects; and the safety of the
research environment.
Applications will compete for available funds with all other
favorably recommended applications.  The following will be considered
when making funding decisions: quality of the proposed project as
determined by peer review, program balance, and availability of
Each sponsoring Institute/Center is identified below.  A staff
contact for electronic and telephone is listed and inquiries
regarding programmatic (research scope, eligibility and
responsiveness) issues are encouraged.  The opportunity to clarify
any issues or answer questions from potential applicants is welcome.
National Institute of Allergy and Infectious Diseases
Division of Allergy, Immunology, and Transplantation
Helen Quill, Ph.D.
Telephone:      (301) 496-7551
Fax:            (301) 402-2571
EMAIL:      hq1t@nih.gov
National Institute of Allergy and Infectious Diseases
Division of Microbiology and Infectious Diseases
Lee Hall, M.D., Ph.D.
Telephone:      (301) 496-2544
Fax:            (301) 402-2508
EMAIL:          lh24g@nih.gov
National Institute of Allergy and Infectious Diseases
Division of Acquired Immunodeficiency Syndrome
Scott Cairns, Ph.D.
Telephone:      (301) 496-8197
Fax:            (301) 402-3211
EMAIL:          sc160p@nih.gov
National Heart, Lung and Blood Institute
Judith Massicot-Fisher, Ph.D.
Telephone:      (301) 435-0504
Fax:            (301) 480-1454
EMAIL:          jm294z@nih.gov
National Institute on Aging
Dr. Anna M. McCormick
Telephone:      (301) 496-6402
Fax:            (301) 402-0010
EMAIL:          am38k@nih.gov
National Institute of Child Health and Human Development
Allan Lock, D.V.M.
Telephone:   (301) 496-5541
Fax:            (301) 402-4083
EMAIL:          locka@hd01.nichd.nih.gov
Research under this announcement will be supported under programs
cited in the Catalog of Federal Assistance (CFDA).  The PHS portion
of the CFDA is available at URL:
http://odphp.osophs.dhhs.gov/cfda/index.htm.  Awards will be
administered under PHS grants policies and Federal Regulations 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.
The Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use 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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