Full Text AI-94-012

AFFECTING GRAFT SURVIVAL WITH DONOR IMMUNE TISSUE

NIH GUIDE, Volume 23, Number 6, February 11, 1994

RFA:  AI-94-012

P.T.


Keywords: 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  April 15, 1994
Application Receipt Date:  June 21, 1994

PURPOSE

The Division of Allergy, Immunology and Transplantation (DAIT) of the
National Institute of Allergy and Infectious Diseases (NIAID) invites
applications for basic, preclinical and clinical studies to increase
knowledge of the interaction between donor and recipient
immunocompetent cells.  These studies have the potential to help
develop protocols for enhancing solid organ graft survival by
infusion of donor cells prior to or after transplantation.
Information from these studies could lead to the use of donor tissue
to manipulate the recipient's immune system in a controlled and
specific fashion, thereby increasing graft survival and improving the
management of autoimmune diseases.

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), Affecting Graft Survival With Donor Immune
Tissue, is related to the priority areas of diabetes and chronic
disabling diseases, and immunization and infectious diseases.
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) 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 clinical transplantation 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 for new applications.  Future
competing renewal applications will compete with all
investigator-initiated applications and will be reviewed according to
customary referral and review procedures.  FIRST awards are not
renewable.

FUNDS AVAILABLE

The estimated funds available for the total (direct and indirect)
first year costs of all awards made under this RFA will be
$1,500,000.  In Fiscal Year 1994, the NIAID plans to fund
approximately seven R01s/R29s.  Applications may not request more
than four percent annual inflationary increases for future years.
The usual 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,
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

Successful transplantation relies on the ability to transplant a
solid organ without rejection while maintaining a normal immune
response to infectious agents.  With the exception of transplants
between identical twins, the only known way to accomplish this is to
induce a specific non-responsive (tolerant) state, whereby the
grafted tissue is ultimately not recognized as foreign.  Donor
specific transplant tolerance has been achieved for solid organ
transplantation in animal models via induction regimens using donor
immunocompetent tissue, e.g., bone marrow and peripheral blood.  The
application of those induction regimens to humans would be served
best by understanding fully the basic immunological mechanisms
involved and the role of the donor immune tissue in inducing and
maintaining this tolerant state.

Tolerance can be categorized into three types:  (1) clonal deletion
(central tolerance), (2) clonal anergy (peripheral tolerance), and
(3) active cellular suppressive mechanisms.  The most stable type of
tolerance is clonal deletion, whereby specific reactive T cells
(i.e., T cells bearing T-cell receptors that recognize the foreign
tissue antigens) have been deleted from the repertoire entirely
through negative selection in the thymus.  The only way to develop an
immune response to the antigen (i.e., "break" this type of tolerance)
is to have selection and expansion of a T cell bearing a T-cell
receptor that cross-reacts with the donor non-self antigens.  The
most reliable way to induce central tolerance is to engraft
allogeneic stem cells.  Donor specific lymphoid cells that develop in
the presence of both host and donor antigens become tolerant to host
antigens.

Clonal anergy is defined as the functional inactivation of
antigen-specific T cells.  Normally, this type of immunological
regulation is thought to be a "fail-safe" mechanism to inactivate
self-reactive T cells that escape clonal deletion in the thymus.  It
has become increasingly obvious that specific inter-and intracellular
signalling events are required to anergize a T cell versus activate
it.  While this mechanism of tolerance undoubtedly plays a major role
in successful transplants in recipients who have long-term graft
survival, anergy was established early in the life of the T cell and
the T cell could still be activated by a non-specific mechanism.  A
breakdown of anergy would lead directly to rejection, e.g., when
opportunistic infections such as CMV stimulate the immune system to
produce IL-2 or by non-specific activation of the quiescent T cells
that are capable of recognizing the graft.

The third mechanism of donor-specific non-responsiveness, active
cellular suppression, is probably the most important for
transplantation.  This active suppression relies on specific cells to
down-regulate the immune response.  For donor-specific
non-responsiveness, the introduction of donor immunocompetent cells
into the recipient appears to specifically turn off the recipient's
immune response to the donor antigens.  Recently, it has been shown
that transfusions of donor blood, prior to transplantation, may
enhance graft survival.  Also, the administration of donor bone
marrow cells, transfused pre- or peri-operatively under the cover of
immunosuppressive agents, induces a donor-specific non-responsiveness
that is transient in humans and has been long-lasting, if not
permanent, in animal models.  Additionally, organs that contain
larger amounts of lymphoid tissue, such as the liver, appear to be
well tolerated immunologically, and it has been suggested that this
"tolerance" may result from the establishment of microchimerism in
the recipient.  This microchimerism has been studied and current
hypotheses are that there is a subset of cells responsible for
inducing and maintaining this tolerant condition.  While progress has
been made in phenotyping the tolerance-inducing donor cell, a number
of important factors remain unclear:  whether this cell is derived
from the T-cell lineage; the in vivo mechanism operative in
tolerance; what constraints for the route of administration exist;
and timing of exposure of the recipient to this cell type in order to
obtain transplant tolerance.

Identification of the cells necessary for the induction and
maintenance of donor-specific tolerance, the mechanisms involved, and
timing of the regimen will greatly enhance human graft survival.

Research Objectives and Scope

The objective of this RFA is to support innovative new research to
characterize the immunocompetent cells responsible for and the
mechanisms by which donor immune tissue or cells enhance graft
survival.  This RFA will support basic, preclinical, and clinical
studies aimed at characterizing the interaction between donor and
recipient immunocompetent cells.  These studies have the potential to
help develop protocols for enhancing graft survival by using an
infusion of donor lymphoid or dendritic cells prior to or after solid
organ transplantation, either alone or in combination with other
agents, to make the recipient non-responsive to the donor.
Information from these studies could lead to the use of donor tissue
to manipulate the recipient's immune system in a controlled and
specific fashion.

Applications should focus on identifying the donor and recipient
cells involved in and the mechanisms responsible for induction and
maintenance of donor-specific non-responsiveness in the transplant
setting.  Areas of particular interest to NIAID include, but are not
limited to, the following:

o  identification of the donor cell(s) involved in the induction and
maintenance of donor-specific non-responsiveness

o  determination of the optimal timing of administration of donor
cells for inducing long lasting donor-specific non-responsiveness

o  determination of the optimal route of administration of the donor
cells for induction of donor specific non-responsiveness

o  evaluation of the role of chimerism in the maintenance of
tolerance (whether it be peripheral microchimerism or any other type
and degree of chimerism)

o  identification of the mechanism(s) by which donor immunocompetent
cells suppress the recipient immune response

   (1) what are the signals necessary to establish the tolerance?
   (2) where is the donor cell exerting its influence on the
recipient immune response, i.e., in the periphery or centrally?
   (3) can donor cells be manipulated to enhance their tolerogenic
capacity?

Animal models must be used in a way that is applicable to human
transplants.  Therefore, although studies using just the infusion of
donor immunocompetent cells may be proposed, this type of study must
be focused on understanding the basic mechanisms of transplant
tolerance induction and maintenance.  Knowledge generated by this
research project must be applicable to human transplantation where an
underlying immunosuppressive regimen is used.  Therefore, studies
proposing to use a monotherapy must also show that currently accepted
standard immunosuppressive regimen is or is not deleterious to the
induction of the tolerant state.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to 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 should 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 should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  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 Sections 1-4 of the Research Plan AND summarized in Section 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,
every effort should be made 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.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned.  Peer reviewers will address
specifically 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
policies.

NOTE:  Peer review groups need adequate information about the
composition of proposed study populations in all applications
involving human subjects.  To avoid delays in review of such
applications, the NIAID therefore requires that, as a minimum, the
application must contain demographic data about the clinic and/or
in-patient population from which study subjects will be drawn:
average hospital admissions per year; percentage distribution of
black/hispanic/other minority/non-minority populations; gender; etc.
Studies using non-hospital populations, such as community-based
studies, should provide similar data about populations in the area or
region from which the study subjects will be drawn. In the absence of
current data, historical demographic information and/or previous
recruitment data for similar studies from the proposed sites should
be provided.

LETTER OF INTENT

Prospective applicants are asked to submit, by April 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 (Program Director), 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. Olivia Preble at
the address listed under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 09/91).  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, MD 20892, telephone (301) 710-0267.  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
"AFFECTING GRAFT SURVIVAL WITH DONOR IMMUNE TISSUE" must be typed in.
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
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.

In preparing the application in response to this RFA, the applicant
should bear in mind the research objectives of this RFA.
Applications should be prepared according to the instructions in form
PHS 398 (rev. 9/91).  Failure to follow these instructions may result
in delays in the review or in an incomplete application.  It is
highly recommended that the Chief of the Genetics and Transplantation
Branch be contacted in the early stages of preparation of the
application.  (See program contact in INQUIRIES below.)

Applications must be received by June 21, 1994.  Applications that do
not conform to the instructions contained in PHS 398 (rev. 9/91)
application kit, will be judged non-responsive and will be returned
to the applicant.  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
staff; those judged to be incomplete will be returned to the
applicant without review.  Those considered to be non-responsive will
be either returned without review or will be referred to the DRG as
unsolicited applications, to be scheduled for initial review at the
next DRG review cycle.

Those applications that are complete and responsive may be triaged by
an NIAID peer review group to determine their relative scientific
merit.  The NIAID will withdraw from competition those applications
judged to be non-competitive for award and will notify the applicant
and institutional business officials.  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.  Applicants may receive
an abbreviated summary statement together with essentially unedited
reviewers' comments.  The second level of review will be provided by
the National Advisory Allergy and Infectious Diseases Council.
Review, Council and award dates are listed below under Schedule.

The factors to be considered in the evaluation of scientific merit of
each application will be those used in the review of traditional
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; and the adequacy and suitability
of the facilities.

While the following 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; the adequacy of protection of human subjects and/or
animals in research; and the adherence to NIH guidelines concerning
adequate representation of women and minorities in clinical 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 to:

Stephen M. Rose, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A14
6003 Executive Boulevard
Bethesda, MD  20892
Telephone: (301) 496-5598
FAX:  (301) 402-2571

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

Olivia Preble, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C19
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8208
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Ms. Barbara Huffman
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C26
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7075

Schedule

Letter of Intent Receipt Date:  April 15, 1994
Application Receipt Date:       June 21, 1994
Scientific Review Date:         October 1994
Advisory Council Date:          February 1995
Earliest Award Date:            April 1995

AUTHORITY AND REGULATIONS

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 Regulations 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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