Full Text PA-97-077
NIH GUIDE, Volume 26, Number 24, July 25, 1997
PA NUMBER:  PA-97-077
P.T. 34

  Transplantation Immunology 

National Institutes of Health
The National Institutes of Health (NIH) invites applications for
studies to further our understanding of the role of minor
histocompatibility antigens (MiHA) in graft vs host disease (GVHD)
following bone marrow transplantation and the possible involvement of
MiHAs in chronic graft rejection of solid organ transplants. Most of
the research efforts to date have centered on the role of the major
histocompatibility complex (MHC) antigens in rejection of
transplanted tissues and organs.  This Program Announcement is
directed at characterizing the immunologic response to MiHA and at
defining the manner and extent to which that response affects
successful long-term engraftment.  The immune response to MiHA is a
major, if under appreciated, cause of graft failure in bone marrow
transplantation.  This initiative is designed to promote research to
characterize the immunologic response to MiHA and to attempt to
define how that response can be prevented to enhance graft survival.
It will support basic, pre-clinical, and clinical studies using
molecular and cellular approaches to dissect the immune response to
these antigens.  These studies may lead to new information with the
potential for clinical applications thereby improving long-term graft
survival in bone marrow and solid organ transplant recipients.
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) 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 award (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
Responsibility for the planning, direction, and execution of the
proposed research for all applicable mechanisms of support will be
solely that of the applicant.
Transplantation of bone marrow and solid organs such as kidney,
heart, liver and lung remains the treatment of choice for several
disease states.  Although recent progress has improved the short-term
survival of allografts, immunological rejection is still an
impediment to long-term survival. Substantial evidence has been
accumulated indicating that matching the donor organ and the patient
for major histocompatibility complex (MHC) antigens can improve both
solid organ and bone marrow graft survival.  However little is known
about the extent to which minor histocompatibility antigen (MiHA)
mis-matches affect graft survival.  For example, in patients who have
been treated to prevent graft rejection, approximately half of
HLA-matched bone marrow recipients develop acute or chronic GVHD and
this is believed to result from MiHA mis-matches. Similarly, while
short-term solid organ transplant survival is positively affected by
MHC matching, long-term graft survival is still poor with only 40% of
kidneys surviving more than ten years.  The role of MiHA mis-matches
in the eventual loss of these grafts is unknown and the subject of
The total number of MiHA loci is unknown and evidence from several
laboratories suggests that there are a limited number of minor
antigenic differences between individuals. It is noteworthy that even
an allelic difference, involving a single conservative amino acid
substitution in a normal protein, can change it into a minor antigen.
A major impediment to the identification and characterization of the
MiHA antigens is that they are not recognized by B cells, resulting
in the inability to produce antibodies to them. The MiHA do, however,
stimulate T cell responses. The nature of the T cells that are
stimulated is an area that requires further investigation and appears
to depend on the specific MiHA that is being recognized. For example,
whereas MHC class I-restricted CD8+ T cells have been generated
against numerous MiHa, MHC class II-restricted responses have been
generated against only a limited number of MiHA.  In addition,
although most of the CD8+ responses can involve class II-restricted,
CD4+ T cell help, several MiHA have been reported to stimulate T
helper cell-independent responses.  It is not known to what extent
the different types of responses impact bone marrow or solid organ
graft survival.
Recent advances in the analysis of MiHA has revealed that the
antigens appear to be MHC class I bound small peptides presented to
alpha-beta T cell receptor (TCR)+ T cells in an MHC-restricted
manner.  Thus, MiHA are recognized with the same degree of
specificity as the major histocompatibility antigens.  Also, recent
studies imply that only a few of the many identified MiHA are
recognized in an allotransplant setting, suggesting that there are
immuno-dominant MiHA. While the relative tissue expression of MiHA
has not been determined, due to the lack of available reagents,
functional analyses using cytotoxic T cells suggest that many MiHA
have a tissue restricted distribution and, thus, only certain tissues
may be at risk for rejection.  Also of interest is the observation
that, in bone marrow transplantation, the clinical picture of MiHA
GVHD resembles several autoimmune diseases, such as systemic lupus
erythematosis and scleroderma, suggesting that the symptoms of
chronic GVHD are  autoimmune-like.  As can be seen from the above
discussion, the immune response to MiHAs is complex and therefore
basic, pre-clinical, and clinical research will be required to
further understand MiHAs and their involvement in GVHD and solid
organ graft rejection.
Research Objectives and Scope
The objectives of this PA are to identify and characterize MiHA and
to determine their role in GVHD and rejection of solid organ grafts.
This information will be used to identify approaches to enhance graft
survival and to test them experimentally.  The scope of research to
be supported under this PA includes, but is not limited to, the
following broad areas of interest and specific examples of
investigations.  The examples are not meant to be directive, but
illustrative of areas that remain to be further investigated.
Therefore, investigators are encouraged to develop novel approaches
to identify and characterize MiHA and the immune response to them.
Relevant topics include, but are not limited to:
o Identification of the genetic loci that encode MiHA and
establishment of techniques to determine the total number of minor
o  Identification of immunodominant minor antigens and  their
antigenic peptides and the mechanism of immunodominance (relative
abundance, affinity of peptide for MHC, affinity of TCR for MHC/MiHA
peptide complex). Also, in vivo correlates of in vitro peptide
immunodominance could be studied to determine if the immunodominant
peptides identified in vitro function similarly in vivo.
o  Analysis of TCR gene usage by responding T cells to determine if
there is heterogeneity or preferential usage in the responding T cell
population.  Correlation of TCR usage with recognition of an
immunodominant antigen.
o  Studies of the relative tissue expression of various  MiHA and the
impact of differential tissue distribution on transplant rejection.
o  Latent viral antigens as a potential source of MiHA.
o  Functional analysis of MiHA-reactive CD8+ T cells and  studies of
the role of CD4+ T cells in the anti-MiHA  response.  Differences
between MiHA antigens that stimulate CD8+ vs CD4+ responses.
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
PA title must 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
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 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 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 Cancer Institute
For NCI basic research:
Anne K. Heath
Telephone:  (301) 496-7815
Fax:        (301) 496-8656
Email:       ah43v@nih.gov
For NCI Clinical Research:
Roy Wu, Ph.D.
Telephone:  (301) 496-8866
Fax:        (301) 480-4663
Email:       WuR@dct.nci.nih.gov
National Institute of Diabetes and Digestive and Kidney
Lawrence Agodoa, M.D.
Telephone:  (301) 594-7717
Fax:        (301) 480-3510
Email:  agodoal@ep.niddk.nih.gov
Research under this announcement will be supported under program
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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