HUMAN ISLET TRANSPLANTATION INTO HUMANS

Release Date:  December 11, 1998

RFA:  DK-99-006

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Allergy and Infectious Diseases
Juvenile Diabetes Foundation International

Letter of Intent Receipt Date:  February 10, 1999
Application Receipt Date:  March 10, 1999

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases, the
National Institute of Allergy and Infectious Diseases (NIAID) and the Juvenile
Diabetes Foundation International (JDFI) invites investigator-initiated research
grant applications to investigate the potential of modulation of the immune
response in humans to transplanted human islets. These applications should
propose clinical studies using new methods to induce immune tolerance to prevent
reoccurrence of the autoimmune destruction of the beta cells in the islet, which
causes type 1 diabetes, and to prevent transplant rejection.  These methods
include anti-CD40 ligand antibody, CTLA4Ig and anti-B7 antibody and/or bone
marrow transplantation to create lymphocyte 'chimerism.' Collaborative efforts
linking expertise in tolerance induction, autoimmunity, transplantation, and
islet isolation to expertise in diabetes are strongly encouraged.

Applications will be submitted to the NIH and will be reviewed by the NIH
according to usual NIH peer review procedures. Applicants wishing to have their
application considered by the JDFI for possible funding must authorize the NIH
to provide a copy of their application and NIH-prepared summary statement of the
initial review to the JDFI.

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), Human
Islet Transplantation Into Humans, is related to one or more of the priority
areas.  Potential applicants may obtain a copy of "Healthy People 2000" at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of the
Federal government. Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research project grant
(R01)and Interactive Research Project Grant (IRPG) award mechanisms.  Guidelines
for preparing IRPG applications are available from the program official or from
the internet at: http://grants.nih.gov/grants/guide/pa-files/PA-96-001.html.

Responsibility for the planning, direction, and execution of the proposed project
will be solely that of the applicant.  The total project period for an
application submitted in response to this RFA may not exceed five years.  This
RFA is one-time solicitation.  Future unsolicited competing continuation
applications will compete with all investigator-initiated applications and be
reviewed according to the customary peer review procedures.  The anticipated
award date is September 30, 1999.

It is anticipated that the award for each site of research activity will be
approximately $750,000 direct costs per year.

Applicants from institutions which have a General Clinical Research Center (GCRC)
funded by the NIH National Center of 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 should
be included with the application.

FUNDS AVAILABLE

The NIDDK intends to commit approximately $3 million, the NIAID intends to commit
approximately $1 million and the JDFI intends to commit approximately $1 million
in FY 1999 to fund 4 to 5 new and/or competitive continuation grants in response
to this RFA. An applicant may request a project period of up to five years and
a budget for direct costs of approximately $750,000 per year, excluding
facilities and administrative costs on consortium arrangements.  Because the
nature and scope of the research proposed may vary, it is anticipated that the
size of each award will also vary. Although the financial plans of the NIDDK and
the NIAID provide support for this program, awards pursuant to this RFA are
contingent upon the availability of funds and the receipt of a sufficient number
of applications of outstanding scientific and technical merit.  At this time, it
is not known if competing renewal applications will be accepted and/or if this
RFA will be reissued.

RESEARCH OBJECTIVES

Background

Diabetes mellitus affects approximately 16 million people in the United States. 
Individuals with type 1 diabetes mellitus have lost their ability to produce
insulin due to immune system-mediated destruction of the insulin producing beta
cells of the pancreas.

On September 4 and 5, 1997, the NIH sponsored a conference entitled "Diabetes
Mellitus: Challenges and Opportunities."  This conference identified research
opportunities in several areas, one of the most important being the need for
innovative therapies for diabetes.  It was noted that intensive treatment of type
1 diabetes, although effective in improving long-term outcome, is difficult to
implement for many patients and does not achieve euglycemia.  The level of
glycemic control achieved using currently available intensive treatment methods
is at best 4-5 standard deviations above the mean value for the nondiabetic
population, as measured by glycated hemoglobin (HbA1c).  Intensive therapy is
also limited by the accompanying increased frequency of severe hypoglycemia and
weight gain, resulting in an increasing prevalence of overweight patients with
type 1 diabetes.

Finally, currently available intensive therapy is  particularly problematic in
children and adolescents due to difficulties in getting them to comply with
current treatment regimens.  This is especially troublesome since current
clinical data support early intervention as being the most effective treatment
strategy.  Thus, the results of the Diabetes Control and Complications Trial
indicate that maintenance of near normal glycemic levels can reduce and delay the
onset of the devastating complications of  diabetes.  Therefore, establishing
methods to achieve and maintain euglycemia will have enormous impact on the
health and quality of life of individuals with diabetes.

Scope and Objectives

Although the ultimate research goal is to prevent the onset of type 1 diabetes,
investigators are currently developing approaches and technology to modulate
blood glucose levels in patients with diabetes and to restore insulin-producing
capacity through transplantation of the whole pancreas, or of islets from the
pancreas.  Today, the only method that offers normal blood glucose levels is
pancreas transplantation.  Several decades ago, islet transplantation was
proposed in the hope of reducing the need for difficult surgical procedures by
allowing intravenous injection of islets.  Initial animal studies on islet
transplantation were encouraging, but subsequent research using larger animals
and humans resulted in lower success rates as defined by exogenous insulin
independence.

Unfortunately, the initial promise held out for islet cell transplantation has
not been realized.  Thus, of the 270 adult islet transplants performed by the end
of 1995 in patients with type 1 diabetes, only ten percent of recipients did not
require insulin injections for more than one week, and only five percent remained
off exogenous insulin for more than one year.  In light of these results, studies
are needed to better understand what treatment regimens would allow successful
islet transplantation using the least amount of immunosuppression, thereby
minimizing the toxicity to the islet.  For example, corticosteroids, a mainstay
of immunosuppressive regimens for solid organ transplantation, interfere with the
normal beta cell function to release insulin in response to elevated blood sugar
levels.  In addition, the recurrence of autoimmune-mediated destruction of
transplanted beta cells is problematic, and many researchers are pursuing studies
to abrogate the underlying autoimmunity that has led to type 1 diabetes.

While the "gold standard" for transplant success has been insulin independence,
clinicians are observing a beneficial effect of islet transplantation even in
recipients who have not achieved insulin independence. These patients require
less exogenous insulin and show an improvement in metabolic control, which
equates to fewer episodes of severe hypoglycemia. This effect may also lower the
risk of long-term complications.

Considerable knowledge has accrued from these early studies, including: improved
procedures for handling the donor pancreas to optimize islet survival; improved
methods for preparing large quantities of islets; the development of standardized
solutions of enzymes to dissociate the islets from the other pancreatic tissue;
pre-transplant treatment methods to reduce rejection; cryopreservation
procedures; and evidence of the detrimental effects of immunosuppressive therapy
on islet function and survival.

New clinical interventions in the autoimmune disease process, which leads to type
1 diabetes, are being developed.  Currently being considered is a strategy
already utilized to block the progression of several autoimmune diseases.  T cell
activation is inhibited with an antibody  that binds to a cell membrane component
(CD28 or CTLA4) of an activating T cell and prevents further T cells from being
activated.  For type 1 diabetes, the intent would be to employ this protocol for
induction of tolerance to transplanted islets, and to prevent further autoimmune
attack on the transplanted islets.  The scope of this RFA includes the
establishment of clinical methods for immunomodulation/tolerance induction and
the establishment of hematopoietic stem cell therapies for immunomodulation.

Relevant topics for study listed below are examples and should not be construed
as required or limiting.

o  Development and evaluation of immunomodulation regimens to optimize patient
safety and promote islet allograft survival

o  Assessment of how to prevent autoimmune destruction of the transplanted islets

o  Optimization of tolerance induction protocols that would allow indefinite
islet survival

o  Determination of the optimal site for islet engraftment to minimize the immune
response and maximize graft function

o  Determination of the optimal number of islets necessary to ensure engraftment,
most efficiently

o  Establishment of methods to completely abrogate the non-specific inflammatory
response to infused islets

Although the NCI will not formally participate in this solicitation, the NCI has
strong interests in studies of anti-CD40 ligand antibody, CTLA4Ig and anti-B7
antibody, blood or bone marrow transplantation to create lymphocyte 'chimerism'
and other issues dealing with tolerance induction and autoimmunity.  Applications
addressing these areas but judged to be non-responsive to the RFA will be of
interest to the NCI, commensurate with established referral guidelines.

SPECIAL REQUIREMENTS

Letter of Authorization

Applicants should submit a brief letter to the NIDDK indicating whether or not
they wish their application to be considered for funding by the JDFI.  While
applicants may request that their applications be considered only by the NIH and
not by the JDFI, it is necessary that the record indicate the applicant's
consideration of this opportunity. For those applicants who wish to have the JDFI
consider their application, all materials relating to the application will be
promptly forwarded to that organization and the summary statements for such
applications will be shared with the JDFI when available.  The NIDDK will provide
no information to the JDFI related to applications from applicants who request
that the JDFI not consider their application.  Letters of authorization should
be prepared by the principal investigator and co-signed by the official signing
for the applicant organization.  This letter may be combined with the Letter of
Intent (see below) or may be submitted as a cover letter accompanying the
application.

In all cases, the NIDDK and NIAID will make their funding decisions prior to
those of the JDFI.

Periodic Meetings

Upon initiation of this program, the NIDDK, the NIAID and the JDFI plan to
sponsor periodic meetings to encourage exchange of clinical results among
investigators, to foster collaborative efforts among program grantees, and to
identify resources that would enhance the productivity of grantees.  For this
purpose, applicants should request travel funds for a two-day meeting each year,
probably held in Bethesda, Maryland.  Applicants should also include a statement
in their applications indicating their willingness to participate in such
meetings and to cooperate with other researchers at other clinical research
sites.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.  This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research," which was published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11,
March 18, 1994, available on the web at:
http://www.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.  This
policy applies to all initial (Type 1) applications submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in
Research Involving Human Subjects that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address:
http://www.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 10, 1999, a letter of
intent that includes a descriptive title of the proposed research; the name,
address, and telephone number of the Principal Investigator; the identities of
other key personnel and participating institutions; and the number and title of
the RFA in response to which the application may be submitted.

Although a letter of intent is not required, is not binding, and does not enter
into the review of a subsequent application, the information that it contains
allows NIDDK staff to estimate the potential review workload and avoid conflict
of interest in the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev.4/98) is to be used in applying
for these grants.  These forms are available at most institutional offices of
sponsored research and from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone 301/435-0714, email: GrantsInfo@nih.gov.

The RFA label available in the PHS 398 application form must be affixed to the
bottom of the face page of the application.  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.  In addition, the RFA title and number must
be typed on line 2 of the face page of the application form and the YES box must
be marked.

If a collaboration of individual investigators is planned, it is necessary to
identify one of the investigators as the group coordinator and to cite this
individual in all applications on page 2 of the form PHS 398 (rev. 4/98).
Applicants who have entered into a collaboration may submit the applications
individually with a cover letter noting their involvement and listing the other
members of the collaboration.  These applications should all include the
DESCRIPTION OF INTERACTIVE RESEARCH ACTIVITIES

Submit a signed, typewritten original of the application, including the
Checklist, and five signed, 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)

Applications must be received by the application receipt date listed in the
heading of this RFA.  If an application is received after that date, it will be
returned to the applicant without review.

The Center for Scientific Review (CSR) 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.  The CSR
will not accept any application that is essentially the same as one already
reviewed.  This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and for
responsiveness by the NIDDK and the NIAID.  Incomplete applications will be
returned to the applicant without further consideration.  If the application is
not responsive to the RFA, CSR staff may contact the applicant to determine
whether to return the application to the applicant or submit it for review in
competition with unsolicited applications at the next review cycle.

Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group in accordance
with the review criteria stated below.  As part of the initial merit review, a
process will be used by the initial review group in which applications receive
a written critique and undergo a process in which only those applications deemed
to have the highest scientific merit, generally the top half of the applications
under review, will be discussed, assigned a priority score, and receive a second
level review by the NIDDK and NIAID National Advisory Councils.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written comments reviewers will be asked to discuss the following aspects of the
application in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application.  Note that the application does not need to be
strong in all categories to be judged likely to have major scientific impact and
thus deserve a high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is essential
to move a field forward.

(1) Significance:  Does this study address an important problem? If the aims of
the application are achieved, how will scientific knowledge be advanced?  What
will be the effect of these studies on the concepts or methods that drive this
field?

(2) Approach:  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

(3) Innovation:  Does the project employ novel concepts, approaches or method?
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

(4) Investigator:  Is the investigator appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the principal investigator and other researchers (if any)?

(5) Environment:  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their subgroups,
and children as appropriate for the scientific goals of the research.  Plans for
the recruitment and retention of subjects will also be evaluated.

o  The reasonableness of the proposed budget and duration in relation to the
proposed research

o  The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project 
proposed in the application.

The initial review group will also examine the provisions for the protection of
human subjects and the safety of the research environment.

IRPG applications will have these additional review criteria:

o  Each component R01 of the IRPG will be reviewed as above for its independent
scientific merit.

o  The reviewers will assess the intended IRPG interactions, including the
effectiveness and feasibility of the proposed IRPG group interactions, whether
or not they enhance the prospects for reaching the stated objectives of the
group, and the extent of synergy among the various projects.

Schedule

Letter of Intent Receipt Date:    February 10, 1999
Application Receipt Date:         March 10, 1999
Peer Review Date:                 June/July 1999
Council Review:                   September 1999
Earliest Anticipated Start Date:  September 30, 1999

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities

INQUIRIES

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:

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:  Joan_Harmon@NIH.GOV

Stephen M. 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:  Steve_Rose@nih.gov

Direct inquiries regarding fiscal matters to:

George A. Tucker, MBA
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 6AN-38A
Bethesda, MD  20892
Telephone:  (301) 594-8853
FAX:  (301) 480-3504
Email:  tuckerg@extra.niddk.nih.gov

Pam Fleming
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C25
Bethesda, MD  20892-7610
Telephone:  (301) 402-6580
FAX:  (301) 480-3780
Email:  pf49e@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.847 and 93.855.  Awards are made under authorization of the Public Health
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-
158, 42 USC 241 and 285) and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health Systems
Agency review.

The PHS strongly encourages all grant 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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