Full Text PA-97-075
NIH GUIDE, Volume 26, Number 24, July 25, 1997
PA NUMBER:  PA-97-075
P.T. 34

  Transplantation Immunology 
  Transplantation of Organs 

National Institutes of Health
The National Institutes of Health invites applications for studies to
further our understanding of the immune response to direct or
indirect presentation of allogeneic major histocompatibility complex
(MHC) antigens and to determine the contribution of each pathway to
acute and chronic graft rejection. Research to date has focused on
direct recognition of allogeneic MHC and therapies designed to block
this pathway have been successful in reducing acute rejection of
transplanted organs.  However, chronic rejection is still an
impediment to long-term survival.  The indirect pathway of
allorecognition has recently been implicated primarily in chronic
graft rejection, however an additional role for this pathway in  the
enhancement of acute rejection has been suggested.  Knowledge from
basic, preclinical and clinical studies aimed at characterizing the
relative role of the direct and the indirect allorecognition pathways
in enhancing or preventing graft rejection could lead to the
development of specific interventions to modulate immune recognition
after transplantation and ultimately increase graft survival.
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 domestic and foreign, 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.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
Traditional research project grant (R01)and FIRST award (R29)
applications may be submitted in response to this program
announcement.  Applications for R01 grants may request up to five
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.
Recognition of allogeneic major histocompatibility complex (MHC)
antigens is still a major impediment to the survival of solid organ
grafts.  Although progress has been made in the short-term survival
of transplants, immunologic rejection is still an impediment to
long-term survival. Direct recognition of allogeneic (MHC) antigens
by T cells had been thought to be the primary cause of acute
rejection of transplanted organs. Indirect recognition results from
self MHC-restricted presentation of donor MHC peptides and occurs
when the allogeneic MHC molecules shed by the donor tissue are taken
up and processed by recipient antigen presenting cells (APC).  This
pathway has recently been implicated in the chronic rejection of
transplanted organs.
The mechanism(s) of rejection mediated by either direct or indirect
recognition are likely to be different.  The direct recognition
pathway involves recognition by recipient T cells of donor allogeneic
MHC class I and class II, resulting in the generation of cytotoxic
and helper T lymphocytes which play a pivotal role in the rejection
process.  For indirect recognition, the precise mechanism(s) by which
recognition of self MHC-restricted, donor MHC peptides initiates or
enhances rejection is not understood since the antigenic MHC-peptide
complex that is recognized is not present on the donor tissue.  Some
evidence suggests that indirect recognition of donor MHC can provide
help for and thus amplify the acute rejection mediated by direct
recognition. Thus the relative contribution of direct and indirect
antigen presentation to acute and chronic rejection is still an
unresolved issue.
Although recognition of alloantigen can lead to deleterious effects
on a graft, there are several examples of tolerance induction
following exposure of the recipient to donor alloantigen prior to
transplantation, either by infusion with whole cells or by treatment
with MHC-derived synthetic peptides. The success of this strategy is
dependent upon the nature and dose of the antigen as well as the
route of administration.  Further investigation is needed to
determine how to control the balance between activation and
unresponsiveness mediated by the direct and/or indirect recognition
of alloantigen.  Thus additional research is needed to distinguish
the contributions of direct and indirect recognition to allograft
survival and to determine how this knowledge could lead to
improvements in existing therapies as well as the development of new
therapies to prolong graft survival.
Research Objectives and Scope
This research focuses on understanding the specificity of T cell
recognition of allogeneic MHC molecules in the transplant setting.
These recognition events are key to understanding subsequent events
leading to allograft rejection and are thus the focal point for
immunotherapeutic intervention aimed at preventing immunologic
rejection of organ and tissue grafts.
The scope of research to be supported under this PA includes, but is
not limited to, the following specific examples of investigation.
The examples are meant to illustrate areas that remain to be
investigated. Investigators are encouraged to develop novel
approaches to study the relative contributions of direct and indirect
alloantigen recognition and their role(s) in the rejection of
transplanted organs.
Specific areas of interest include, but are not limited to:
o  analysis of the contribution of indirect alloantigen recognition
in the initiation and/or amplification of acute and chronic graft
o  identification of the antigen presenting cells involved in direct
and indirect presentation and the nature of the T cell responses that
are generated;
o  development of methods to specifically modulate the indirect
antigen recognition pathway to prevent graft rejection, including
combined strategies to modulate both direct and indirect recognition;
o  definition and molecular characterization of  tolerance induction
by pretreatment with alloantigen or alloantigen-derived peptides; and
o  effect of delayed antigen recognition on activation of the direct
or indirect pathway in acute and chronic rejection.
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 for 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:
asknih@odrockm1.nih.gov.  The PHS 398 application kit can be accessed
from the World Wide Web at the following URL:
For purposes of identification and processing, item 2 on the face
page of the application must be marked "YES".  The PA number and the
title must also be typed in section 2.
The completed, signed original and five legible, single-sided copies
of the application must sent or delivered to:
BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)
FIRST (R29) award 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.
Applicants from institutions that have a General Clinical Research
Centers (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 and applications deemed unresponsive will be returned to
the applicant without further consideration.
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 be asked to comment on the following
aspects of the application 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
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
Janet M. Connolly, Ph.D.
Telephone: (301) 496-5598
Fax:       (301) 402-2571
EMAIL:     jc333b@nih.gov
National Heart Lung and Blood Institute
LeeAnn Jensen, Ph.D.
Telephone:  (301) 435-0066
Fax:        (301) 480-1060
Email:       lj15x@nih.gov
National Institute of Diabetes and Digestive and Kidney
Lawrence Agodoa, M.D.
Fax:        (301) 480-3510
Email:  agodoal@ep.niddk.nih.gov
National Institute of Arthritis and Musculoskeletal and Skin
Susana Serrate-Sztein, M.D.
Telephone:  (301) 594-5032
FAX:  (301) 480-4543
Email:  szteins@ep.niams.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:
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 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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