NONHUMAN PRIMATE TRANSPLANT TOLERANCE COOPERATIVE STUDY GROUP

Release Date:  January 29, 1999

RFA:  AI-99-003

P.T.

National Institute of Allergy and Infectious Diseases
National Center for Research Resources
National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  March 15, 1999
Application Receipt Date:  May 6, 1999

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID, the National
Center for Research Resources (NCRR), and the National Institute of Diabetes
and Digestive and Kidney Diseases (NIDDK) invite applications from single
institutions or consortia of institutions to participate in a multi-center,
cooperative research program to evaluate existing and new tolerance induction
treatment regimens and to elucidate the underlying mechanisms of the
induction, maintenance and/or loss of tolerance in nonhuman primate models of
kidney and islet transplantation. The goals of this research program are to:
(1) evaluate further the safety, toxicity and efficacy of existing tolerance
induction regimens; (2) evaluate the safety, toxicity and efficacy of new
tolerance induction regimens; (3) define the underlying mechanisms of action
of the therapeutic approaches under investigation; and (4) develop and
validate immune and/or surrogate markers of the induction, maintenance and
loss of tolerance, graft function, graft acceptance and graft survival. All
applicants must comply with the requirements outlined in the section below
titled "SPECIAL REQUIREMENTS."

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),
NONHUMAN PRIMATE TRANSPLANT TOLERANCE COOPERATIVE STUDY GROUP, 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 Summary Report: Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington, DC 20402-
9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
organizations; public and private institutions, such as universities,
colleges, hospitals, laboratories, units of State and local governments; and
eligible agencies of the Federal government.  Foreign institutions are not
eligible to apply.  Racial/ethnic minority individuals, women, and persons
with disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The administrative and funding mechanism to be used to undertake this program
will be the Multi-project Cooperative Agreement (U19), an "assistance"
mechanism, rather than an "acquisition" mechanism, in which substantial NIH
scientific and/or programmatic involvement with the awardee is anticipated
during the performance of the activity.  Under the cooperative agreement, the
NIH purpose is to support and/or stimulate the recipient's activity by
involvement in and otherwise working jointly with the award recipient in a
partner role, but it is not to assume direction, prime responsibility, or a
dominant role in the activity.  Essential elements of the Multi-project
Cooperative Agreement mechanism also include:  (1) a minimum of three inter-
related individual research projects organized around a central theme; (2)
collaborative efforts and interaction among independent projects and their
investigators to achieve a common goal; (3) a single Principal Investigator
who will be scientifically and administratively responsible for the group
effort; (4) a single applicant institution that will be legally and
financially responsible for the use and disposition of funds awarded; and (5)
support provided, as necessary, for "core" resources or facilities, each of
which is expected to be utilized by at least two research projects in order to
facilitate the research efforts.  Details of the responsibilities,
relationships, and governance of a study funded under cooperative agreement(s)
are discussed later in this document under the section Terms and Conditions of
Award.

The total project period for applications submitted in response to this RFA
may not exceed five years.  At present, the NIAID is administratively limiting
the duration of Multi-project Cooperative Agreements to four years; this
administrative limitation may change in the future.  At this time, the NIAID
has not determined whether and how this solicitation will be continued beyond
the present RFA.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for the first
year of support for all awards made under this RFA will be $2,000,000.  In
Fiscal Year 1999, the NIH plans to fund at least two awards.  The usual PHS
policies governing grants administration and management will apply.  Although
this program is provided for in the financial plans of the participating
institutes, awards pursuant to this RFA are contingent upon the availability
of funds for this purpose and the receipt of a sufficient number of
applications of high scientific merit.  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

Transplantation is now routine therapy for end-stage renal disease, with one-
year graft survival approaching 90% using standard immunosuppressive therapy.
However, long-term graft survival has not improved appreciably since the early
1980s and only about 45% of cadaveric kidneys survive ten years post-
transplant. For other organs (e.g., liver, lung and pancreas), graft survival
does not approach this level. While new immunosuppressive drugs have reduced
acute rejection in the first year post-transplant, it is clear that these
therapeutic improvements will not significantly alter long-term clinical
outcomes. Therefore, much recent attention has focused on the potential for
the induction of donor-specific immune tolerance to achieve long-term graft
survival without the need for non-specific, life-long immunosuppressive
therapy that has deleterious and often life-threatening side effects. Although
certain promising tolerogenic molecules have been shown to induce donor-
specific tolerance in animal models, and are being tested in humans for the
treatment of selected autoimmune diseases, these approaches have not been
rigorously evaluated for transplantation.

The cosponsors of this RFA are the lead NIH components supporting research
focused on immunology, diabetes, kidney and liver diseases, including the
development of improved therapies to prevent these diseases and treat their
complications as well as the development of nonhuman primate resources for
studies leading to further understanding of human health problems and disease
processes.

The NIAID has made immune tolerance a high scientific priority and in the fall
of 1997, NIAID initiated a scientific planning process designed to accelerate
research in this area. A broad-based, long-range NIAID Plan for Research on
Immune Tolerance is available at:
http://www.niaid.nih.gov/publications/immune/bookcover.htm

The NIAID Expert Panel for Research on Immune Tolerance enthusiastically
endorsed the conceptual framework, scope and timeliness of the plan and
encouraged the NIAID to take a leadership role in designing and directing
major research programs in tolerance, particularly with respect to the
application of tolerance induction strategies for the treatment of human
disease. NIAID convened a second expert panel, The NIAID Expert Panel on
Ethical Issues in Clinical Trials of Transplant Tolerance, which concluded
that ethically acceptable human tolerance induction protocols can be developed
and recommended that the NIAID pursue clinical research in kidney and islet
transplantation. In addition, both Expert Panels and the Expert Review Panel
for NIAID's Extramural Transplantation Research Program identified nonhuman
primate tolerance research as an essential step to provide "...critical data
on safety, toxicity and potential efficacy that can not be obtained ethically
in human clinical trials."

In response to these recommendations and current scientific opportunities, the
NIAID will support multiple programs to accelerate the clinical application of
tolerance induction strategies to prevent and treat immune-mediated diseases.
One effort is the establishment of the Collaborative Network for Clinical
Research on Immune Tolerance, a collaborative consortium of institutions that
will conduct clinical trials and integrated studies of underlying mechanisms
focused on the induction and maintenance of immune tolerance to treat multiple
immune system diseases, including: autoimmune diseases; asthma and allergic
diseases; and graft rejection in kidney and islet transplantation. This RFA is
the second endeavor in this area and establishes the Nonhuman Primate
Transplant Tolerance Cooperative Study Group to obtain proof of concept,
safety and toxicity data as well as pursue studies of underlying mechanisms
of, and appropriate immune/surrogate markers for the induction, maintenance
and loss of tolerance.

Studies of existing and new tolerogenic treatment regimens in nonhuman primate
models of kidney and islet transplantation are critical to the design of
scientifically sound and ethically acceptable clinical trials. In addition,
nonhuman primate studies are especially useful as they closely approximate the
human immune system and physiology and these studies allow collection of
important samples necessary to provide information necessary for validation of
new noninvasive or minimally invasive diagnostic tests for tolerance, graft
function, graft survival and graft rejection.

Research Objectives and Scope

The purpose of this RFA is to support a multi-site cooperative research
program to investigate existing and new tolerance induction protocols in
nonhuman primate models of kidney and islet transplantation. For purposes of
this RFA, immune tolerance is defined as a selective lack of an immune
response to targeted antigens that is accomplished by any of a variety of
approaches, including: deletion, induction of anergy, immune deviation,
sequestration, or suppression.  Targets may include antigen-specific
receptors, molecules of the co-stimulation pathways, homing molecules, or
other relevant molecules; and may use a variety of agents, including:
antigens, peptides, altered peptides, monoclonal antibodies, cytokines,
molecularly engineered cells or tissues, DNA vectors, or other relevant
approaches.

All participating sites will utilize uniform controlled study designs and
standardized data collection procedures. Specifically, each member of the
cooperative research program will design and conduct:

o  Studies of the safety, toxicity and efficacy of existing and new tolerance
induction regimens to improve graft survival and/or prevent graft rejection,
including pre-, peri-, and post-transplant tolerogenic therapies to induce
donor-specific tolerance: (1) alone; (2) in combination with standard
immunosuppressive therapy; (3) in combination with new immunosuppressive
therapies; and (4) in combination with immunosuppressive therapy withdrawal. 
Major scientific approaches to immune tolerance include, but are not limited
to, the following:

--Co-stimulatory blockade (e.g., anti-CD40 ligand antibody, anti-B7 antibody,
CTLA4-Ig)
--Cytokine modulation (e.g., IL-4, IL-12, TNF, TGF()
--Clonal deletion (e.g., Fas-ligand)
--Other approaches such as leukocyte migration blockade, peptide-based
therapies targeted at specific antigens, and the use of molecularly engineered
cells and tissues for deletion or inactivation of pathogenic lymphocytes.

o  Studies of the underlying mechanisms of action of the therapeutic
approaches being evaluated, including changes in immune response and function,
measures of the induction, maintenance and loss of donor-specific tolerance. 
Possible approaches to the study of underlying mechanisms include, but are not
limited to, the following:

--Quantitation of disease-related, alloreactive T lymphocytes using methods
such as MHC/peptide tetramers, chimeric antibodies, or very early activation
antigens;

--Analysis of alloreactive T cells for expression of genes implicated in
immunity or inflammation, or by FACS for cell surface markers that identify
functions (e.g., cytokine receptors that distinguish Th1 from Th2 or chemokine
receptors or integrins that indicate preferential patterns of homing);

--Use of new technologies, (e.g., Magnetic Resonance Imaging and other non-
invasive diagnostic and monitoring techniques; high throughput technologies
such as gene chips using expressed sequence tags to identify and evaluate the
function of genes activated at sites of rejection); and

--Comparison of samples from peripheral blood and urine with those from sites
of rejection.

o  Studies to develop, evaluate and validate standardized, reliable and
sensitive immune and/or surrogate markers of the induction, maintenance and/or
loss of tolerance, short- and long-term graft function, graft survival and
graft rejection, with particular emphasis on defining clinically relevant
predictors of acute and chronic rejection.  This includes establishing
appropriate measures (e.g., lymphokines or cytokines and/or their receptors,
lymphocyte subsets, etc.), selecting appropriate samples (e.g., blood, urine,
biopsies, etc.), and selecting appropriate techniques (e.g., quantitative PCR,
gene chip technology, imaging, cellular immune assays, etc.) for routine use. 
Possible markers include: changes in gene or protein expression in blood,
urine or biopsy materials; antibody or cytokine levels in blood, urine or
biopsies; or in vitro lymphocyte responsiveness to donor antigens as
determined by proliferation, cytotoxic activity, or antibody or cytokine
secretion.

Under this RFA, support will not be provided for research focused on improving
the quality and/or supply of islets for transplantation.  This includes
developmental work to produce improved islets and technologies for immune
isolation through approaches such as encapsulation. In addition, cross-species
transplantation is not within the scope of this RFA. Costs associated with the
procurement of nonhuman islets, however, will be supported under this RFA.

SPECIAL REQUIREMENTS

A.  Study Organization

1.  Steering Committee

A Steering Committee will be established to serve as the main governing body
of the Nonhuman Primate Transplant Tolerance Cooperative Study Group
(hereafter referred to as the Cooperative Study Group).  At a minimum, the
Steering Committee will be composed of the NIAID Coordinator, the Principal
Investigators, the Chair of the Adjunct Studies Subcommittee (see below), and
a Statistical Coordinator for each Cooperative Study Group. If the awardee is
a consortium of institutions, one additional investigator from the consortium
will serve on the Steering Committee as a permanent member, or on a rotating
basis, if appropriate, as determined by the protocols under development or
implemented.

A broad range of scientific and technical expertise is required to carry out
the objectives of this RFA, including extensive experience in: the study of
immune-mediated diseases, transplantation immunobiology and genetics, nonhuman
primate models of immune system disorders, solid organ, cell and tissue
transplantation, molecular and cellular biology, particularly as applied to
the identification and evaluation of biomarkers and assay development and
validation, and research design and statistics.  The Cooperative Study Group
must include scientific expertise in these areas under the direction of a
senior scientist, serving as the Principal Investigator, with responsibility
for the scientific, technical and administrative coordination and management
of the Cooperative Study Group.

All major scientific decisions will be determined by the Steering Committee,
with each Principal Investigator, additional investigators, Chair of the
Adjunct Studies Subcommittee, and the NIAID Coordinator.  A Chairperson will
be selected by the Steering Committee from among the non-federal members
during the first meeting of the Committee, to be convened by the NIAID
Coordinator.  The Committee will meet at least twice during the first 12
months of the project and annually thereafter.

The Steering Committee will have primary responsibility for developing the
common treatment protocols, approving the design and implementation of all
adjunct studies, facilitating the conduct and monitoring of all studies,
analyzing and interpreting study data, and reporting study results.  Studies
will proceed to the implementation stage only with the concurrence of the
Steering Committee.  Each Steering Committee member will be expected to
participate in all other Steering Committee activities, e.g., conference
calls, special subcommittees as may be necessary, etc.

The Steering Committee shall appoint an Adjunct Studies Subcommittee to
design, implement and evaluate (1) studies of underlying mechanisms of action
of the therapeutic approaches under investigation, and (2) studies to develop,
evaluate and validate immune and/or surrogate markers of the induction,
maintenance and/or loss of tolerance, graft survival, graft function and graft
rejection. The members of the Adjunct Studies Subcommittee shall be selected
by the Principal Investigators, with each Principal Investigator appointing
two Subcommittee members, and shall include the NIAID Coordinator as a voting
member.  The Chair of the Adjunct Studies Subcommittee shall be elected from
among the non-federal members and shall serve as a voting member of the
Steering Committee.  The Subcommittee will meet in conjunction with Steering
Committee meetings twice during the first 12 months of the project and
annually thereafter.  Subcommittee members will be expected to participate in
all meetings and in other Subcommittee activities, e.g., conference calls.

Other subcommittees of the Steering Committee may be established as necessary.

NIAID will facilitate collaboration and coordination between the Nonhuman
Primate Transplant Tolerance Cooperative Study Group and the Collaborative
Network for Clinical Research on Immune Tolerance, to be established in the
fall of 1999 under the cosponsorship of NIAID, the National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK), and the Juvenile Diabetes
Foundation International (JDFI).  This Collaborative Network will be composed
of a consortium of institutions focused on the study of immune tolerance in
humans, including:  (1) clinical trials of tolerance induction in kidney
transplantation, islet transplantation and autoimmune diseases; (2) integrated
studies of the mechanisms underlying the induction, maintenance and loss of
tolerance in humans; and (3) the development, evaluation and validation of
biomarkers and assays to measure immune tolerance in humans.  Close
coordination among these two research programs will facilitate the development
of safety, toxicity and potential efficacy data from nonhuman primate
transplant models critical to the design and implementation of scientifically
sound and ethically acceptable human trials for both existing and new
tolerogenic approaches.  Close coordination will also enable the application
of findings from nonhuman primates to the clinical setting with respect to
important immune/surrogate markers and reliable assays to measure tolerance. 
The annual meetings of the Nonhuman Primate Transplant Tolerance Cooperative
Study Group Steering Committee will include a joint session with the Executive
Committee of the Collaborative Network for Clinical Research on Immune
Tolerance and involve dissemination and review of interim and final data,
overall study progress, and approved but not implemented, ongoing and future
studies relevant to the design of human clinical trials. The Request for
Proposals to establish the Collaborative Network for Clinical Research on
Immune Tolerance (RFP NIH-NIAID-DAIT-99-30) is available at the NIAID
Contracts Management homepage (http://www.niaid.nih.gov/contract/rfp's/rfp9930.htm).

In addition, the Principal Investigators of the Cooperative Study Group and
the Chair of the Adjunct Studies Subcommittee will report on progress and
future plans to the NIAID Advisory Committee for Research on Immune Tolerance
at its annual meeting.  This will include the preparation of data and other
written materials addressing the current status of research projects,
preliminary and final results, and proposed future investigations.

2.  Data Coordination and Management

Each Cooperative Study Group member institution will be responsible for its
own data collection, management and quality assurance.  Specific data analyses
to be carried out will be determined by the Steering Committee, will be
conducted by the Statistical Coordinator(s), and the results of those analyses
will be delivered to the Steering Committee as the group responsible for
determining if and what further analyses should be performed, how the results
are interpreted, whether the results impact ongoing data collection or future
studies, and how the findings should be disseminated. Applicants should
request support for all data collection and analyses, including a Statistical
Coordinator in their budget.

B. Terms and Conditions of Award

The following terms and conditions will be incorporated into the award
statement and provided to the Principal Investigator as well as the
institutional official at the time of award.

These special Terms of Award are in addition to, and not in lieu of, otherwise
applicable OMB administrative guidelines, HHS Grant Administration Regulations
at 45 CFR part 74 and 92, and other HHS, PHS, and NIH Grant Administration
policy statements.

The administrative and funding instrument used for this program is the Multi-
project Cooperative Agreement (U19), an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH scientific and/or
programmatic involvement with the awardee is anticipated during the
performance of the activity.  Under the Multi-project Cooperative Agreement,
the NIH purpose is to support and/or stimulate the recipient's activity by
involvement in and otherwise working jointly with the award recipient in a
partner role, but it is not to assume direction, prime responsibility, or a
dominant role in the activity.

Consistent with this concept, the dominant role and prime responsibility for
the activity resides with the awardees for the project as a whole, although
specific tasks and activities in carrying out the research will be shared
among the awardees and the NIAID Coordinator.

1.  Awardee Rights and Responsibilities

Awardees will have primary responsibility for defining the research
objectives, approaches and details of the projects within the guidelines of
the RFA and for performing the scientific activity. Specifically, awardees
have primary responsibility as described below.

Steering Committee Membership and Meeting Attendance

Each Principal Investigator, additional investigators, where appropriate, and
Statistical Coordinator from an applicant consortium will serve as a voting
members of the Steering Committee and will participate in all scientific
decisions.  Each Steering Committee member will be responsible for attending
all Steering Committee meetings, including not less than two meetings during
the first 12 months of the study and annually thereafter, and participate in
all other Steering Committee activities, e.g., conference calls, special
subcommittee meetings as may be necessary, etc.

Subcommittees of the Steering Committee may be established as necessary.  At a
minimum, the Steering Committee will establish an Adjunct Studies Subcommittee
to provide advice to the Steering Committee with respect to research on
immune/surrogate markers for induction, maintenance and loss of tolerance,
graft function and graft survival, as described under the section "RESEARCH
OBJECTIVES."  The Adjunct Studies Subcommittee will be composed of two
representatives selected by each Principal Investigator, as well as the NIAID
Coordinator.  This Subcommittee will meet annually in conjunction with the
Steering Committee meeting.

Protocol Development and Conduct

The Steering Committee, or a separate Study Design Subcommittee, will define
the objectives and approaches of all treatment protocols and adjunct studies
and design the consensus protocols to be implemented by the Cooperative Study
Group. Each institution participating in the Cooperative Study Group will
follow the procedures required by the consensus protocol generated by the
Steering Committee or its appointed Study Design Subcommittee regarding study
conduct and monitoring, data collection and quality control.

Data Coordination and Management

Each Cooperative Study Group member institution will be responsible for its
own data collection, management and quality assurance. Specific data analyses
to be carried out will be determined by the Steering Committee, will be
conducted by the Statistical Coordinator(s), and the results of those analyses
will be delivered to the Steering Committee as the group responsible for
determining which further analyses should be performed, how the results are
interpreted, whether the results should influence ongoing data collection or
future studies, and how the findings should be disseminated. Applicants should
include in their budget requests support for all data collection and analyses,
including a Statistical Coordinator.  The awardees will retain custody of and
have primary rights to all data developed under these awards, subject to
Government rights of access consistent with HHS, PHS, and NIH policies.

Publication and Presentation of Study Findings

Early publication of major findings is encouraged.  Publications and oral
presentations of work performed under this agreement will require appropriate
acknowledgment of both the Cooperative Study Group and NIH support.  Analyses
to be performed using the collective data from the Cooperative Study Group
institutions will be determined and directed by the Steering Committee. 
Cooperative Study Group institutions wishing to perform analyses of local data
will inform the Steering Committee of any such analyses prior to initiation in
order to avoid duplication.  Review and approval by the Steering Committee
will be required for all analyses prior to publication or presentation
according to criteria that will be developed by the Steering Committee. The
Steering Committee may establish a Publications Subcommittee to serve this
function.

Monitoring Study Progress

The Steering Committee will establish mechanisms for assessing performance of
the Cooperative Study Group institutions.  This includes quality, accuracy and
timeliness of data collection and management, conscientious observance of
study requirements, and presentation of study results at joint meeting with
the Executive Committee of the Collaborative Network for Clinical Research on
Immune Tolerance and the NIAID Advisory Committee for Research on Immune
Tolerance.

Federally Mandated Regulatory Requirements

The PHS Policy on Humane Care and Use of Laboratory Animals requires that
applicant organizations proposing to use vertebrate animals file a written
Animal Welfare Assurance with the Office for Protection from Research Risks,
establishing appropriate policies and procedures to ensure the humane care and
use of live vertebrate animals involved in research activities supported by
the PHS. The PHS policy stipulates that an applicant organization, whether
domestic or foreign, bears responsibility for the humane care and use of
animals in PHS-supported research activities.

All institutions are required to comply, as applicable, with the Animal
Welfare Act as amended (7 USC 2131 et sec.) and other Federal statutes and
regulations relating to animals. These documents are available from the Office
for Protection from Research Risks, National Institutes of Health, Bethesda,
MD 20892, (301) 496-7163.

2.  NIAID Staff Responsibilities

NIAID staff assistance will be provided by the Chief of the Genetics and
Transplantation Branch, Division of Allergy, Immunology and Transplantation,
NIAID who will serve as NIAID's Coordinator. The NIAID Coordinator will have
substantial scientific/programmatic involvement during the conduct of this
activity through technical assistance, advice and coordination above and
beyond normal program stewardship for grants, as described below.

Steering Committee Membership and Meeting Attendance

The NIAID Coordinator will serve as a voting member of the Steering Committee,
will attend all Steering Committee meetings, and will participate in other
Committee activities, e.g., conference calls, special subcommittees.  The
NIAID Coordinator will also serve on the Adjunct Studies Subcommittee.

Protocol Development

As a member of the Steering Committee, the NIAID Coordinator and other NIH
representatives will serve as a resource with respect to the design of
treatment protocols and adjunct studies and will assist the Steering Committee
in study development.

Study Materials

The NIAID Coordinator will be responsible for obtaining and distributing study
materials to be used in the treatment protocol developed by the consensus of
the Steering Committee.

The NIAID is not responsible for obtaining or distributing of solid organs,
tissues or cells to be used by the Cooperative Study Group.

Monitoring Study Performance

The NIAID Coordinator will provide assistance to the Steering Committee in the
development of mechanisms and procedures for monitoring study performance. 
This includes the accuracy, quality and timeliness of data collection and
management, consistency in observing study requirements, and presentation of
study results at joint meetings with the Executive Committee of the
Collaborative Network for Clinical Research on Immune Tolerance and the NIAID
Advisory Committee for Research on Immune Tolerance.

Data Coordination and Management

Each Cooperative Study Group member institution will be responsible for its
own data collection, management and quality assurance. Specific data analyses
to be carried out will be determined by the Steering Committee, will be
conducted by the Statistical Coordinator(s), and the results of those analyses
will be delivered to the Steering Committee as the group responsible for
determining if and what further analyses should be performed, how the results
are interpreted, whether the results impact ongoing data collection or future
studies, and how the findings should be disseminated. Applicants should
include in their budget requests support for all data collection and analyses,
including a Statistical Coordinator.  The awardees will retain custody of and
have primary rights to all data developed under these awards, subject to
Government rights of access consistent with HHS, PHS, and NIH policies.

The Government, via the NIAID Coordinator, will have access to data generated
under this Multi-project Cooperative Agreement and may periodically review the
data and progress reports.  NIAID Staff may use information obtained from the
data for the preparation of internal reports on the activities of the study. 
However, awardees will retain custody of and have primary rights to all data
developed under these awards.

Publication and Presentation of Study Findings

The NIAID Coordinator and other NIH representatives may contribute, through
review, comment, analysis, and/or co-authorship, to reporting results of the
studies conducted by the Cooperative Study Group to the investigator community
and other interested scientific and lay organizations.  Co-authorship by the
NIH staff will be subject to approval in accordance with NIH policies
regarding staff authorship of publications resulting from extramural awards.

Organizational Changes

Certain organizational changes require the prior written approval of the NIAID
Coordinator.  These changes include the addition or replacement of a
scientific investigator, affiliate, component, or research base that is
associated with this study.  A change in the Principal Investigator, or in any
key personnel identified on the Notice of Award, must have the prior written
approval of the NIAID Grants Management Specialist in consultation with the
NIAID Coordinator.

Program Review

The NIAID Coordinator will review the progress of the Cooperative Study Group
through consideration of annual progress reports, periodic reports on ongoing
progress, findings and future plans presented during meetings and conference
calls, publications, site visits, etc. This review may include, but is not
limited to, compliance with the study protocols, adherence to uniform data
collection procedures and participation in Steering Committee and other
committee meetings as necessary.

The NIAID reserves the right to terminate or curtail the study (or any
individual award) in the event of (a) a major breech of the protocols, (b)
substantive changes in the agreed-upon protocols to which the NIAID does not
agree, and/or (c) reaching a major study endpoint substantially before
schedule with persuasive statistical significance.

3.  Collaborative Responsibilities

A Steering Committee, composed of the Principal Investigators, additional
investigators, the Statistical Coordinators, and the NIAID Coordinator will be
the main governing body of the Cooperative Study Group and will have primary
responsibility for all scientific decisions, including: defining protocol
objectives and approaches; designing and implementing protocols; developing
procedures for data collection, management and quality control; establishing
procedures for assessing performance with respect to adherence to protocols
and adjunct studies; analyzing and interpreting study data; and
publishing/presenting study findings.  Each member of the Steering Committee
will have one vote.  The chairperson will be selected by the Steering
Committee from among the non-federal members.  Subcommittees will be
established by the Steering Committee, as it deems appropriate.  At a minimum,
the Steering Committee will establish an Adjunct Studies Subcommittee to
provide advice with respect to the mechanistic research and immune/surrogate
marker studies as described under "RESEARCH OBJECTIVES."

Cooperative Study Group institutions will be required to accept and implement
the common treatment protocols, adjunct studies and procedures approved by the
Steering Committee.  Studies will proceed into the implementation stage only
with the concurrence of the Steering Committee, the NIAID Coordinator and
other NIH representatives.

4.  Arbitration

Any disagreement that may arise on scientific or programmatic matters (within
the scope of the award) between award recipients and the NIAID may be brought
to arbitration.  An arbitration panel will be composed of three members -- one
selected by the Steering Committee (with the NIAID member not voting) or by
the individual awardee in the event of an individual disagreement, a second
member selected by the NIAID, and the third member with expertise in the
relevant area and selected by the two prior members will be formed to review
any scientific or programmatic issue that is significantly restricting
progress.  While the decisions of the Arbitration Panel are binding, these
special arbitration procedures will in no way affect the awardee's right to
appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50,
subpart D, and HHS regulations at 45 CFR Part 16.

Cooperative agreements are subject to the administrative requirements outlined
in OMB circulars A-102 and A-110.  All pertinent HHS, PHS, and NIH grant
regulations, policies and procedures, with particular emphasis on PHS
regulations at 42 CFR Part 52 and HHS regulations at 45 CFR Part 74, are
applicable. These special terms and conditions pertaining to the scope and
nature of the interaction between the NIAID and the investigators will be
incorporated in the Notice of Grant Award.  However, these terms will be in
addition to, not in lieu of, the customary programmatic and financial
negotiations that occur in the administration of cooperative agreements.

LETTER OF INTENT

Prospective applicants are asked to submit, by March 15, 1999, a letter of
intent that includes a descriptive title of the overall proposed research; the
name, address and telephone number of the Principal Investigator and all
collaborators; 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 NIH 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. Bela Gulyas at the address listed under
INQUIRIES.

APPLICATION PROCEDURES

Applicants for U19 cooperative agreements must follow special application
guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR
MULTI-PROJECT AWARDS (September 1997); this brochure is available via the WWW
at: http://www.niaid.nih.gov/ncn/grants/multibron.htm.

Application kits are available at most institutional offices of sponsored
research and may be obtained from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email:
[email protected].  Application kits are also available on the World Wide Web
at: http://www.nih.gov/grants/forms.htm.

For purposes of identification and processing, item 2 on the face page of the
application must be marked "YES" and the RFA number "AI-99-003" and the words
"Non-human Primate Transplant Tolerance Cooperative Study Group" must be
entered on the face page.

Applications must be received by May 6, 1999.  Applications that are not
received as a single package on the receipt date or that do not conform to the
instructions contained in PHS 398 (rev. 4/98) Application Kit (as modified in,
and superseded by, the special instructions below, for the purposes of this
RFA), will be judged 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.

If the application submitted in response to this RFA is substantially similar
to a grant application already submitted to the NIH for review, but that has
not yet been reviewed, the applicant will be asked to withdraw either the
pending application or the new one.  Simultaneous submission of identical
applications will not be allowed, nor will different review committees review
essentially identical applications.  Therefore, an application that is
essentially identical to one that has already been reviewed cannot be
submitted in response to this RFA.  This does not preclude the submission of
substantial revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.

It is highly recommended that the appropriate NIAID program contact be
consulted before submitting the letter of intent and during the early stages
of preparation of the application.  (See program contacts under INQUIRIES).

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

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional exact copies of the grant
application and all five sets of any appendix material must be sent to Dr.
Bela Gulyas at the address listed under INQUIRIES.  DUE TO THE EXPEDITED
NATURE OF THIS RFA, FAILURE TO SEND THESE ADDITIONAL COPIES COULD RESULT IN AN
APPLICATION NOT BEING INCLUDED IN THE PEER REVIEW PROCESS.

Minimum Requirements for Application

To promote the development of a collaborative program among the award
recipients, a minimum number of issues need to be addressed in the
applications, as outlined below.

1.  The application must include a broad-based scientific agenda designed to
evaluate the safety, toxicity and efficacy of various tolerogenic approaches
in nonhuman primate models of kidney and islet transplantation with the goal
of inducing immunosuppression free, donor-specific tolerance to improve graft
function, graft survival and prevent graft rejection, and to delineate the
mechanisms involved in the induction, maintenance and loss of tolerance as an
integral part of the treatment protocols.  The scientific agenda shall include
the following:

a)  A discussion of the state-of-the-art of research focused on elucidating
the underlying mechanisms of immune tolerance and on evaluating tolerogenic
approaches in nonhuman primate studies and human clinical trials.

b)  A description of gaps in knowledge and scientific opportunities relevant
for the application of tolerogenic approaches to nonhuman primate studies and
human clinical trials in kidney and islet transplantation.

c)  A plan to accelerate research on immune tolerance in nonhuman primate
models of kidney and islet transplantation, including:

(1)  A conceptual framework delineating approaches to tolerance induction to
improve graft survival and prevent graft rejection, priorities among various
approaches and the rationale for such priorities, including potentially
promising reagents and molecules in development;

(2)  The relevance of each approach to human kidney and islet transplantation;

(3)  A conceptual framework for delineating underlying mechanisms of
tolerogenic approaches through studies conducted as an integral part of the
nonhuman primate treatment protocols;

(4)  A description of promising nonhuman primate treatment protocols,
including the rationale for the selection of tolerogenic approaches, and
overall study design; and

(5)  A description of promising mechanistic studies to be incorporated as an
integral part of the nonhuman primate treatment protocols, including the
rationale for the selection of the mechanistic studies, proposed techniques,
and the overall design of such studies.

(6)  A plan detailing the acquisition and preparation, if applicable, of the
solid organs, tissues or cells to be used in the studies. All costs required
for this must be included in the application and fully justified.

2.  The application must also include:  (1) a 1-2 page synopsis for each of
two proposed pilot treatment protocols to assess safety and efficacy and
incorporating two mechanistic studies, and (2) a 1-2 page synopsis for each of
two proposed efficacy treatment protocol incorporating 3 mechanistic studies
(all synopses are to be included as appendices).  Since the actual treatment
protocols to be performed will be selected by the Steering Committee, the
final protocols implemented by the Cooperative Study Group may not reflect any
protocol submitted in response to this RFA. Budget requests should reflect and
fully justify all costs associated with the conduct of the above studies.

3.  The application must include at least two proposed adjunct studies, each
focused on the development, evaluation and validation of sensitive immune
and/or surrogate markers of the induction, maintenance or loss of tolerance
and short- and long-term graft function, survival and/or rejection.  Proposed
adjunct studies are to include: identification of and rationale for the immune
and/or surrogate markers selected, including published data from laboratory,
animal and human studies; description of and rationale for the proposed
source, quantity and number of samples required; methodologies proposed to
collect and analyze samples; and a discussion of how the results of the
proposed adjunct studies will contribute to improvements in the capacity to
utilize immune and surrogate markers to predict the induction, maintenance or
loss of tolerance, graft function and graft survival. Proposed studies using
new technologies, including minimally and non-invasive approaches are
encouraged.  Since the actual adjunct studies to be performed will be selected
by the Steering Committee, the final studies carried out by the Cooperative
Study Group may not reflect any single adjunct study submitted in response to
this RFA.  All costs required for the proposed adjunct studies must be
included in the application and must be fully justified.  These include the
additional costs for all proposed adjunct studies and data collection and
analyses.

4.  The application must identify the single applicant organization that will
be legally and financially responsible and accountable for the use and
disposition of funds awarded on the basis of this RFA to other institutions
participating in the consortium, if applicable, and show availability of
personnel and facilities capable of performing and supporting the
administrative functions necessary.

5.  The application must name a single Principal Investigator (PI) who will
have scientific responsibility for the application as a whole, including all
consortium-related research activities, if applicable.  The PI must be a
senior scientist with substantial experience related to the scope and
objectives of the RFA.  In addition, applications from a consortium of
institutions must designate a single investigator for each participating
institution who will be responsible for on-site scientific implementation,
direction and management of the studies, as well as the coordination of
requirements for adjunct studies of underlying mechanisms and immune/surrogate
markers.

6.  Applications must also demonstrate the scientific and technical expertise
required to design, conduct and analyze treatment protocols, mechanistic
studies and assay development and validation.

7.  Applications must provide: a clear, concise plan, in narrative and
diagrammatic form, that depicts the interrelationships among the research
projects and the scientific and technical staff, their relevant
experience/expertise, and the contribution of each to fulfillment of the
objectives of this RFA; an organizational chart of the consortium showing the
name, organization, and scientific discipline of the PI and of all key
scientific, technical and administrative personnel; and a mechanism for
selecting and replacing key professional or technical personnel.

8.  If the application is from a consortium, it must provide a plan to assure
the maintenance of close cooperation and effective communication among members
of the consortium, including letters of commitment to this plan from all
participating institutions.

9.  The application should discuss the capability of the applicant
organization and each institution in a consortium, if applicable, to
participate and interact effectively in cooperative, multi-center studies.

10.  The application must include a written commitment to accept the
participation and assistance of NIH staff in accordance with the guidelines
outlined under "Terms and Conditions of Award: NIAID Staff Responsibilities." 
The application must also include a written commitment to the cooperative
organization and willingness to serve on the Steering Committee and adhere to
the decisions reached by that Committee, including following the consensus
treatment protocols and adjunct studies.

REVIEW CONSIDERATIONS

Review Procedures

Upon receipt, applications will be reviewed for completeness by the Center for
Scientific Review (CSR) and for responsiveness by NIAID staff.  Incomplete
and/or non-responsive applications will be returned to the applicant without
further consideration.  Applications that are complete and responsive to the
RFA will be evaluated for scientific and technical merit by an appropriate
peer review group convened by the NCRR in accordance with the review criteria
stated below.  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 applications under review, will be discussed, assigned a priority
score, and receive a second level review by the National Advisory Allergy and
Infectious Diseases Council.

Review Criteria

The review criteria for U19 multiproject cooperative agreement applications
are presented in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR
MULTI-PROJECT AWARDS (September 1997); this brochure is available via the WWW
at: http://www.niaid.nih.gov/ncn/grants/multibron.htm.

The initial review group will also examine: the appropriateness of proposed
project budget and duration, the provisions for the protection of animal
subjects; and the safety of the research environment.

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and technical merit
as determined by peer review, program balance, and the availability of funds. 
The earliest anticipated date of award is September 10, 1999.

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 (research scope and eligibility)
issues to:

Stephen Rose, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4A14
Bethesda, MD  20892-7640
Telephone:  (301) 496-5598
FAX:  (301) 402-2571
Email: [email protected]

Jerry A. Robinson, Ph.D.
Comparative Medicine
National Center for Research Resources
6705 Rockledge Drive, Suite 6030
Bethesda, MD 20892
Telephone: (301) 435-0744
FAX: (301) 435-3819
Email: [email protected]

Joan T. Harmon, Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 5AN-18G
Bethesda, MD  20892
Telephone:  (301) 594-8813
FAX:   (301) 480-3503
Email:  [email protected]

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

Dr. Bela Gulyas
Division of Extramural Activities
National Center for Research Resources
6705 Rockledge Drive, Room 6018
Bethesda, MD  20892-7965
Telephone:  (301) 435-7965
FAX:  (301) 480-3660
Email:  [email protected]

Direct inquiries regarding fiscal matters to:


Pamela G. Fleming
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C25
Bethesda, MD  20892-7610
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 402-6580
FAX:   (301) 480-3780
Email:  [email protected]

Schedule

Letter of Intent Receipt Date:  March 15, 1999
Application Receipt Date:       May 6, 1999
Scientific Review Date:         June-July 1999
Advisory Council Date:          September 2, 1999
Earliest Award Date:            September 10, 1999

AUTHORITY AND REGULATIONS

This program is supported under authorization of the Public Health Service
Act, Sec. 301 (c), Public Law 78-410, as amended.  The Catalogue of Federal
Domestic Assistance Citation is Sec. 93.856, Microbiology and Infectious
Diseases Research, No. 93.855 - Immunology, Allergy, and Transplantation
Research, insert additional citations for cosponsors.  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 and contract
recipients to provide a smoke-free workplace and promote the non-use of all
tobacco products. In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or, in some cases, any portion
of a facility) in which regular or routine education, library, day care,
health care or early childhood development services are provided to children. 
This is consistent with the PHS mission to protect and advance the physical
and mental health of the American people.

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