Full Text AI-93-01


NIH GUIDE, Volume 21, Number 39, October 30, 1992

RFA:  AI-93-01

P.T. 34

  Transplantation Immunology 
  Immune System 

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  December 15, 1992
Application Receipt Date:  March 10, 1993


The Division of Allergy, Immunology and Transplantation, National
Institute of Allergy and Infectious Diseases (NIAID), invites
applications for Program Projects on Transplantation Immunology and
Immunogenetics.  The ultimate goal of the research to be conducted is
to achieve the ability to induce a long lasting unresponsiveness that
is specific for the organ/tissue donor as well as for the recipient
of transplanted immuno-competent tissues.  The objective of the
research should be to characterize the regulatory mechanisms involved
in allorecognition and responsiveness and to utilize this information
to develop approaches toward induction of a donor- (or host-, where
relevant) specific non-responsive state.  This program is intended to
stimulate collaboration among transplant clinicians, clinical
scientists, basic immunologists, and immunogeneticists in studies of
the immune system attendant to allogeneic transplantation.  Such
studies may involve:  identification and characterization of genetic
elements regulating the allogeneic response; elucidation of the
cellular and molecular mechanisms involved in both the induction and
effector phases of the allogeneic response; evaluation of the
relevance of graft rejection or graft-versus-host disease to the
development of donor-specific anergy or tolerance; characterization
of the mechanisms by which donor lymphoid tissue induces an
allogeneic response and its potential role in the development of
long-term non-responsiveness; and the development of therapeutic
procedures for inducing long-term graft survival.  This Request for
Applications (RFA) is a reannouncement with modified scope of RFA
AI-91-14 published in the NIH Guide for Grants and Contracts, Vol.
20, No. 33., September 6, 1991. Additional reannouncement is possible
in the future depending on programmatic needs in this area and the
availability of funds.


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 RFA,
Program Projects on Transplantation Immunology and Immunogenetics, 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 202-783-3238).


Applications may be submitted by 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.  Foreign organizations
are not eligible to apply.  Applications from minority individuals
and women are encouraged.


This RFA will use the National Institutes of Health (NIH) Program
Project (P01) grant mechanism.  A P01 is awarded to an institution on
behalf of a Principal Investigator for the support of a broadly
based, multidisciplinary, long-term research program with a specific
major goal or central theme.  A P01 generally involves the organized
efforts of a group of investigators who conduct research projects
related to the overall program goal.  The grant may provide support
for the projects and for certain central resources shared by
individuals in the program project if sharing facilitates the total
research effort.  Each project supported under a program project
grant is expected to contribute to and be directly related to the
common theme of the program.  The projects, each under the direction
of a Project Leader, must demonstrate an essential element of unity
and interdependence.

The application must clearly explain how the projected
multidisciplinary, integrated program can be expected to accomplish
the stated goal more efficiently and effectively than could a series
of independent, individual grant-supported studies.

Designation of a Principal Investigator as Program Director must be
based upon accomplishment and experience as a scientist, the ability
to assume both the leadership of the research group and the
responsibility for scientific, professional, and administrative
functions, and the commitment of a significant amount of his/her time
to the project.  Each Project Leader must have a demonstrable record
of accomplishment in immunology, immunogenetics, or one of the basic
science disciplines or clinical specialties relevant to the
particular subject of investigation.  However, the participation of
one junior, but independent, investigator whose project is an
integral part of the overall program and whose work would be closely
related to that of one of the senior scientist project leaders of the
P01 is encouraged by the NIAID.

The total project period for applications submitted in response to
this RFA may not exceed five years.  At this time, the NIAID is
administratively limiting the duration of such grants to four years;
this administrative limitation may change in the future.  The
earliest anticipated award date is September 1993.  If by the end of
the third year award the NIAID has not announced its intention to
readvertise the RFA, incumbents who wish to recompete may consider
reapplying using the Interactive Research Project Grant (IRPG)
mechanism, if it has been announced.  All applicants at that time are
strongly encouraged to contact NIAID Program Staff prior to
submitting an application.  Budget requests should be limited to no
more than $500,000 total direct costs per annum.  Applications with
an annual budget request in excess of this amount will require
approval by senior NIAID officials via the program officer for
acceptance of the application for processing.  Direct cost funds may
be utilized to support the research activities of technical and
professional personnel, consultation services, equipment, supplies,
travel, and publication costs.  Support for research-related costs of
patient involvement and medical care may be authorized.  No funds
will be provided for new construction; therefore, adequate physical
facilities must be available for the primary needs of the project.
However, moderate alterations or renovations to enhance clinical or
laboratory facilities may be allowed if they are necessary to meet
objectives of the proposed program.


The estimated total funds available for the first year of support for
this RFA will be $1,500,000.  In Fiscal Year 1993, the NIAID plans to
award at least two program project grants submitted in response to
this RFA and, depending on availability of funds and scientific
merit, possibly more than two.

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, 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.



The Genetics and Transplantation Branch of the Division of Allergy,
Immunology and Transplantation, NIAID, supports fundamental studies
and applied research in immunogenetics and transplantation
immunology.  This RFA seeks to stimulate collaboration among
transplant clinicians, clinical scientists, basic immunologists and
immunogeneticists in studies of the immune system in allogeneic

Despite advances in immunosuppressive therapy, the major barrier to
successful engraftment in the transplantation of solid organs and
tissues is the allogeneic immune response which results in graft
rejection or graft versus host disease.  Currently, non-specific
immunosuppression is accompanied by increased risks of infection as
well as by a variety of deleterious side effects, including
nephrotoxicity, hypertension, hyperlipidemia and bone disease.  Even
with the current armamentarium of immunosuppressive agents, problems
with acute graft rejection and failure to achieve long-term graft
survival persist.  Thus, the ultimate goal is to achieve the ability
to induce a long-lasting unresponsiveness which is specific, not only
for the organ or tissue being transplanted, but also to the
host-recipient of transplanted immunocompetent tissue (e.g., bone
marrow or solid organs with passenger leukocytes).  Recent major
advances in the understanding of molecular and cellular processes in
immunology which are integral to the science of transplantation
include:  the identification, cloning, and sequencing of the genes
encoding the T-cell receptor; the elucidation of the
three-dimensional structure of the transplantation antigens encoded
by the major histocompatibility complex (MHC) and the cloning and
sequencing of MHC genes; production of monoclonal antibodies with
specificity for T lymphocyte subpopulations; and the identification
of T-cell derived cytokines and their cell surface receptors.  These
major conceptual advances should allow further clarification of the
complex regulatory mechanisms involved in the acceptance or rejection
of allografts.

Transplant recipients subjected to manipulation of their immune
systems, by means of immunomodulation and, by the graft itself,
constitute a unique resource and opportunity for investigation of the
basic biology of the human immune system which has been deliberately
disturbed.  Basic science studies using these recipients could
provide invaluable guidance to the clinician due to a better
understanding of the immunological events that occur during
transplantation and subsequent medical treatment, as well as the
elucidation of the mechanisms controlling these immunological events.

Applications should emphasize collaborative research between
clinicians and basic scientists using up-to-date concepts and
techniques for the evaluation of the immune system in allogeneic
transplantation.  Applicants are encouraged to emphasize or
investigate:  new ideas and innovative research approaches likely to
lead to the acquisition of new knowledge about the immune system's
ability to respond to the graft; methods to specifically suppress the
immune response without totally immunocompromising the recipient; the
state of the immune system using current immunosuppressive protocols;
and the immune system's ability to respond to natural or test agents.
Although the NIAID stresses the transfer of knowledge from basic
research to clinical applications, preclinical studies involving
laboratory animals are encouraged.

The application should consist of a multidisciplinary research
program that has a well-defined central research focus or objective.
As with all program project grants, there should be a minimum of
three inter-related individual component projects, and all projects
must contribute to the overall theme and objective of the program.
Moreover, the application must clearly explain how the planned
multi-disciplinary approach can be expected to accomplish the stated
goal more efficiently and effectively than a series of independent,
individual research grant-supported studies.


The objectives of the research are to characterize the regulatory
mechanisms involved in allorecognition and responsiveness and to
utilize this information to develop approaches toward induction of a
donor- (or host-, where relevant) specific non-responsive state.
These studies could include an evaluation of the immune status of the
transplant recipient both prior to and after transplantation and
should be directed at characterizing the specific mechanisms
responsible for observed changes.

Appropriate approaches emphasizing the induction of clinical
tolerance/antigen-specific unresponsiveness leading to the long-term
survival of organ allografts must be stressed.  These might include,
but are not restricted to:

o  investigations of the cellular and molecular mechanisms
responsible for the induction of the immune response to organ
allografts and the modification of this response with agents that act
on:  macrophages (or their organ specific equivalents); specific
T-cell subsets; T-cell products (e.g., lymphokines) and cell surface
receptors (e.g., the IL-2 receptor);

o  investigations on molecular genetic manipulation of specific
lymphocyte populations for in vivo therapeutic procedures;

o  characterization of the regulatory interactions between different
populations of lymphocytes (a) of the host in reactivity against
donor tissue; (b) of the donor in graft-versus-host reaction; and (c)
of both donor and recipient in situations that involve two-way cell

o  the utilization of anti-idiotypic reagents in the regulation of
the immune response to allografts; and

o  identification of minor histocompatibility systems and measurement
of their impact on rejection.



NIH policy requires that applicants for NIH clinical research grants
and cooperative agreements 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 must 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 MUST be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale
for its choice.  In addition, gender and racial/ethnic issues should
be addressed in developing a research design and sample size
appropriate for the scientific objectives of the study.  This
information should be included in the form PHS 398 in items 1-4 of
the Research Plan AND summarized in item 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
United States racial/ethnic minority populations [i.e., Native
Americans (including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics].  The rationale for
studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), 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,
clinical samples which may be coded for use by the applicant but
could be identified by another source are not excluded. Every effort
should be made and documented 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.

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

Peer reviewers will specifically address 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


Prospective applicants are asked to submit, by December 15, 1992, a
letter of intent that includes a descriptive title of the overall
proposed research, the name, address and telephone number of the
Principal Investigator (Program Director), a list of the names of key
investigators and their institution(s), 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 NIAID 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. Mark Rohrbaugh at
the address listed under INQUIRIES.


Applications are to be submitted on the standard 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
"Program Projects on Transplantation Immunology and Immunogenetics"
should be typed in.  The program project application must be
submitted as a single package by the applicant organization, and not
as separate, individual projects.

These forms may be obtained from most institutional sponsored
research offices and 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; and from Dr.
Mark Rohrbaugh at the address listed under INQUIRIES.

Applications must be received by march 10, 1993.  Applications that
are not received as a single package from the applicant organization
by March 10, 1993, or that do not conform to the instructions
contained in PHS 398 (rev. 09/91) application kit, will be judged to
be non-responsive 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.

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

Application Receipt Office
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
application must also be sent to Dr. Mark Rohrbaugh at the address
listed under INQUIRIES.

In addition, it is highly recommended that the Chief of the
Transplantation Section, Dr. Andrea A. Zachary (301) 496-5598, be
contacted in the early stages of preparation of the application:
(See program contact listed under INQUIRIES)


General review considerations are outlined in the NIAID Information
Brochure on Program Projects and Centers, which contains special
instructions for preparing multiproject applications for Program
Projects.  It includes REVIEW PROCEDURES and REVIEW CRITERIA for
multicomponent interdisciplinary projects and other important
information.  This Brochure will be sent to applicants upon request.

Upon receipt, applications will be reviewed for completeness by the
NIH Division of Research Grants (DRG) and for responsiveness by NIAID
staff; those judged to be incomplete or non-responsive will be
returned to the applicant without review.

Those applications that are complete and responsive may be subjected
to a triage by an NIAID peer review group before or during the
scientific review meeting to determine their scientific merit
relative to other applications received in response to this RFA.  The
NIAID will withdraw from competition those applications judged to be
non-competitive for award and will notify the applicant and
institutional business officials after transmittal of summary
statements for competitive applicants.

Those applications judged by the reviewers to be competitive for
award will be further reviewed for scientific and technical merit by
a review committee convened by the Division of Extramural Activities,
NIAID, during June 1993.  The second level of review will be provided
by the National Advisory Allergy and Infectious Diseases Council in
September 1993.  September 1993 will be the earliest starting date of

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.  In such a case, a letter of agreement from
either the GCRC Program Director or the Principal Investigator of the
GCRC must be included with the application.

Review Criteria

The general criteria are those review criteria for large,
multicomponent, interdisciplinary program projects as outlined in the
NIAID Brochure on Program Projects, Centers, and Cooperative
Agreements.  Additional scientific/technical merit criteria specific
to the objectives of this RFA are:

1.  Evidence that the proposed Program Director is an established
scientist in the fields of immunology, immunogenetics, or one of the
basic science disciplines or clinical specialties relevant to the
particular subject of investigation with the experience necessary to
assume both leadership of the investigative group and responsibility
for scientific and administrative functions.  Evidence that each
proposed project has a designated project leader with a demonstrated
record of scientific accomplishment in the basic science disciplines
or clinical specialties relevant to the proposed research.

2.  The application of up-to-date concepts and techniques to the
evaluation of the immune system in allogeneic transplantation and the
extent to which the proposed research is able to use new ideas and
innovative approaches to develop new knowledge that will be relevant
to clinical transplantation.

3.  The extent to which the proposed projects are relevant to the
major scientific theme or goal, demonstrating an essential element of
unity and interdependence, and how the proposed multidisciplinary,
integrated program can be expected to accomplish the stated goal more
efficiently and effectively than could a series of independent,
individual grant- supported studies.

4.  A description of the laboratory and clinical facilities available
for use by the proposed project and the adequacy of such facilities.

5.  A description of ongoing and past research conducted by members
of the investigative group and evidence of its relevance to the
proposed projects, identifying existing projects and sources of

6.  The sponsoring institution's commitment to support the
participating investigators in their collaborative and cooperative
efforts to carry out the proposed projects.

7.  Presentation of a clear, concise plan that describes the
interrelationships among the members of the proposed projects and the
contribution of each to the fulfillment of the major goal of the
application.  This should include an organizational chart showing the
name, organization, and scientific disciplines of the key personnel.

8.  For proposed clinical studies, specific information on the
institution's present patient load, documentation of the availability
of adequate patient populations for proposed clinical studies, and
experience in the recruitment and retention of such study
populations.  Documentation of special efforts to recruit women and
under-represented minorities in study populations.

9.  Collaborative arrangements with other laboratories and
investigators and degree of interaction and collaboration among the
project leader(s), consultants, and collaborators.


The earliest possible date of award is September 1993.  Funding
decisions will be made on the basis of scientific and technical merit
as determined by peer review, program needs and balance, and the
availability of funds.


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 in the RFA to:

Andrea A. Zachary, Ph.D., Chief, Transplantation Section
Genetics and Transplantation Branch
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A13
Bethesda, MD  20892
Telephone:  (301) 496-5598
FAX:  (301) 402-0175

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

Mark Rohrbaugh, Ph.D., Scientific Review Administrator
Microbiology & Immunology Review Section
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C22
6003 Executive Boulevard
Bethesda, MD  20892 (Rockville, 20852 if using overnight delivery
Telephone:  (301) 496-8424
FAX:  (301) 402-2638

Direct inquiries regarding fiscal 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


Letter of Intent Date:     December 15, 1992
Application Receipt Date:  March 10, 1993
Scientific Review Date:    June 1993
Advisory Council Date:     September 1993
Earliest Award Date:       September 1993


This program is described in the Catalog of Federal Domestic
Assistance No. 93.855, Immunology, Allergy and Transplantation
Research.  Awards 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 Regulation 42 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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