Full Text PA-97-089
NIH GUIDE, Volume 26, Number 26, August 8, 1997
PA NUMBER:  PA-97-089
P.T. 34

  Transplantation Immunology 
  Transplantation of Organs 

National Institute of Allergy and Infectious Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
National Heart, Lung and Blood Institute
The National Institute of Allergy and Infectious Diseases (NIAID),
the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), and the National Heart, Lung and Blood Institute (NHLBI)
invite applications to enhance our ability to transplant organs and
tissues across species barriers (xenotransplantation) by increasing
our understanding of:  the human immune response to antigens present
on the surface of organs or tissues from non-human species, and the
development of methods to allow rapid identification and treatment of
infectious diseases that might occur by transmission of disease
causing organisms across species barriers.  This research would lead
to the development of new therapies to allow xenografts to survive
and function in humans and the generation of new, sensitive detection
methods to decrease the risk of infectious disease associated with
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 Program
Announcement (PA), Mechanisms of the Immune Response to
Xenotransplant Antigens, is related to the priority areas of
immunization and infectious diseases, diabetes and chronic disabling
disease, and heart disease and stroke.  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) through
the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-0325 (telephone 202-512-1800).
Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of state and local
governments, and eligible agencies of the Federal government.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) grants.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
Traditional research project grants (R01) and FIRST award (R29)
applications may be submitted in response to this PA.  Applications
for R01 grants may request up to five years of support; applications
for R29 grants must request five years of support.  Responsibility
for the planning, direction, and execution of the proposed research
for all applicable mechanisms of support will be solely that of the
Annually, there are more than 40,000 patients waiting for transplants
of kidneys (35,000+), hearts (3,500+), and lungs (2,000+).  In 1995,
19,100 people received transplants of these organs and, currently,
there are shortages of all organs.  Nine patients per day die waiting
for an organ transplant.  The shortage of human organs has led the
transplant community to examine the possibility of using non-human
organs.  The first modern attempt at cross-species organ
transplantation was in 1964, transplanting kidneys from chimpanzees
into patients with renal failure.  While the transplanted kidneys
functioned initially, patients experienced acute rejection and
infectious complications.  One patient survived with a functioning
chimpanzee kidney for nine months.  The same year, a series of
baboon-to-human kidney transplants was attempted with the same
results, acute rejection and infection.  The kidneys functioned while
the patients remained alive.  Twenty years later, the Baby Fae baboon
heart transplant was attempted, using the new, highly effective
immunosuppressive agent Cyclosporin A.  Still, the heart failed after
20 days due to acute rejection.  Other isolated cases of clinical
xenotransplantation have been attempted, all leading to graft failure
or patient death due to infection.
Due to worries about transmission of infectious organisms, especially
viruses, from non-human primates to humans, the pig may become the
organ donor of choice.  However, there are major problems to
overcome.  Humans have preformed antibodies called xenoreactive
natural antibodies (XNA).  These XNA include IgM, IgG and IgA and
appear in the early neonatal period following coliform bacterial
colonization of the large bowel.  Most XNA recognize bacterial cell
wall associated carbohydrates, and are reactive primarily against the
terminal Gal-alpha-1,3-Gal moiety.  These XNA mediate hyperacute
rejection (HAR) of pig organs transplanted in non-human primates via
activation of complement.  The hallmarks of the HAR are hemorrhage,
widespread thrombosis (particularly involving platelets) and ischemia
leading to organ failure within minutes of engraftment.
Recent research advances may hold promise for stopping or
ameliorating the antibody mediated HAR.  The use of soluble
carbohydrate inhibitors to block the recognition of the xenograft by
the preformed XNA has shown limited success in animal models,
improving graft survival from days to weeks.  In addition, use of
Decay Accelerating Factor (DAF) in the recipient has effectively
stopped the complement-induced damage to the xenograft in some model
systems.  Currently, transgenic DAF animals are being bred to try to
extend the success of intravenous DAF therapy.  Other methods being
tested include "knockout" pigs missing the gene for the protein
responsible for addition of the terminal carbohydrate moiety, and
transgenic pigs that contain the genes for human regulator(s) of
complement activation (RCA) to prevent complement damage to the
While current efforts are focused on preventing HAR, there is growing
evidence that a vigorous immune response is still mounted to the
non-human organ beyond the HAR response.  This Delayed Xenograft
Rejection (DXR), or acute vascular rejection, is characterized by
mononuclear cell infiltrates, focal infarcts and interstitial
hemorrhage with intravascular coagulation.  This damage is due to a
series of steps involving mononuclear and endothelial cell
activation, cytokine expression and platelet and fibrin deposition,
leading to xeno-organ rejection within a few days.  While there are
new, exciting results that will allow xenografts to survive longer,
much is still unknown about the immune response to organs from
non-human species.
Another major concern in xenotransplantation is the transmission of
infectious organisms.  Transmission of pathogens, such as swine
influenza, from animal reservoirs to humans is well documented in
settings other than transplantation.  Evolutionary adaptation of
pathogenic organisms to a wider host range is also well documented.
When infectious agents are transmitted from natural hosts to new
species, unpredictable changes in the pathogenic potential of these
infectious organisms can result.  This inter-species infectivity is a
problem for xenotransplantation.  The infectious disease research
that could be supported by this PA is intended to increase our
knowledge of and our ability to characterize the infectious organisms
and processes involved in xenotransplantation.  This would include
the use of modern molecular biological techniques to develop new
diagnostic methods to detect potential pathogens before animal organs
or tissues are transplanted.
Research Objectives and Scope
The objectives of the research to be supported under this PA are to:
delineate the mechanisms and pathology of the delayed xenograft
response to antigens found on the surface of non-human organs,
tissues or cells that might be used for transplantation into humans;
develop new specific and rapid diagnostic tests to identify potential
pathogenic organisms; and quantify the risk of xenogeneic infection.
The scope of research to be supported under this PA includes, but is
not limited to, the following broad areas of interest and specific
examples of investigations.  These examples are not meant to be
inclusive, but rather illustrative of areas that require further
investigation.  Investigators are encouraged to develop novel
approaches to identify and characterize the human immune response to
non-human organs or tissues.
o  Identification of xenoantigens which are immunogenic, such as
Major Histocompatibility Complex (MHC) antigens, Minor
Histocompatibility Complex (MiHC) antigens, and other cell surface
o  Definition of the modes of interaction between xenoantigens and
recipient MHC;
o  Assessment of the risk of transmission of Xenozoonosis
(xeno-infectious disease) in immunocompromised hosts;
o  Development of new diagnostic methods to detect xenozoonoses
before they become frank infections;
o Studies involving genetic manipulation of the donor animal to
either render it less immunogenic or more resistant to the host
immune response;
o Elucidation of the inflammatory events in delayed xenograft
o Studies of the role of adhesion molecules on the host cell types;
e.g. macrophages, NK cells and endothelial cells;
o  Studies in animal models of in vivo safety and efficacy of
antimicrobial therapeutics in immunocompetent and immunocompromised
hosts compared with the in vitro sensitivity of the organisms; and
o  Development of model systems to study the impact of viral mutants,
alterations in pathogenicity, infectivity and transmissibility of
xeno-infectious organisms in immunocompromised hosts.
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 are
provided that inclusion is inappropriate with respect to the health
of the subjects of the purpose of the research.  This policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research", which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and the NIH
Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994.
Applications are to be submitted on the grant application for PHS 398
(rev. 5/95) and will be accepted on the standard application
deadlines as indicated on the application kit.  Applications 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 301/435-0714, email:
For purposes of identification and processing, item 2 on the face
page of the application must be marked "YES".  The PA number and the
PA title must also be typed in section 2.
The completed, signed original and five legible, single-sided copies
of the application must be sent or delivered to:
BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)
R29 applications must include at least three sealed letters of
reference attached to the face page of the original application.
FIRST applications submitted without the required number of reference
letters will be considered incomplete and will be returned without
Applicants from institutions that have a General Clinical Research
Centers (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the Center as a resource for
conducting the proposed research.  If so, a letter of agreement from
the GCRC Program Director must be included in the application
Review Procedures
Applications will be assigned on the basis of established PHS
referral guidelines.  Upon receipt, applications will be reviewed for
completeness by the Division of Research Grants.  Incomplete
applications will be returned to the applicant without further
consideration.  Applications will be reviewed for scientific and
technical merit by study sections of the Division of Research Grants,
NIH, in accordance with the standard NIH peer review procedures.  As
part of the initial merit review, all applications will receive a
written critique and undergo a process in which only those
applications deemed to have the highest scientific merit, generally
the top half of the applications under review, will be discussed,
assigned a priority score, and receive a second level review by the
appropriate national advisory council.
Review Criteria
(1) Significance: Does this study address an important problem?  If
the aims of the application are achieved, how will scientific
knowledge be advanced?  What will be the effect of these studies on
the concepts or methods that drive this field?
(2) Approach: Are the conceptual framework, design, methods, and
analyses adequately developed, well-integrated, and appropriate to
the aims of the project?  Does the applicant acknowledge potential
problem areas and consider alternative tactics?
(3) Innovation: Does the project employ novel concepts, approaches or
method?  Are the aims original and innovative?  Does the project
challenge existing paradigms or develop new methodologies or
(4) Investigator: is the investigator appropriately trained and well
suited to carry out this work?  Is the work proposed appropriate to
the experience level of the principal investigator and other
researchers (if any)?
(5) Environment: Does the scientific environment in which the work
will be done contribute to the probability of success?  Do the
proposed experiments take advantage of unique features of the
scientific environment or employ useful collaborative arrangements?
Is there evidence of institutional support?~
The initial review group will also examine: the adequacy of plans to
include both genders and minorities and their subgroups as
appropriate for the scientific goals of the research and plans for
the recruitment and retention of subjects; the provisions for the
protection of human and animal subjects; and the safety of the
research environment.
Applications will compete for available funds with all other
favorably recommended applications.  The following will be considered
when making funding decisions:  quality of the proposed project as
determined by peer review, program balance, and availability of
Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
Inquiries regarding programmatic issues may be directed to:
Stephen M. Rose, Ph.D.
Chief, Genetics and Transplantation Branch
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A14
6003 Executive Blvd.
Bethesda, MD 20892-7640
Telephone: (301) 496-5598
FAX:  (301) 402-2571
EMAIL:  sr8j@nih.gov
Judith Massicot-Fisher, Ph.D.
Heart Failure SRG Leader
Division of Heart and Vascular Diseases
National Heart, Lung and Blood Institute
6701 Rockledge Drive  MSC 7940
Bethesda, MD. 20892-7940
Telephone:  (301) 435-0504
Fax:  (301) 480-1454
EMAIL:  jm294z@nih.gov
Joan T. Harmon, Ph.D.
Chief, Diabetes Research Section,
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 5An-18G
Bethesda, MD  20892-6600
Telephone:  (301) 594-8813
FAX:  (301) 480-3503
Email:  harmonj@ep.niddk.nih.gov
Direct inquiries regarding fiscal matters to:
Laura Eisenman
Grants Management Branch
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B23
6003 Executive Blvd.
Bethesda, MD 20892-7610
Telephone: (301) 496-7075
Fax:  (301) 480-3780
Email:  le55d@nih.gov
William W. Darby
Heart Section
Grants Management Officer
Grants Operations Branch
National Heart, Lung and Blood Institute
6701 Rockledge Drive
Room 7128, MSC 7926
Bethesda, MD 20892-7926
Telephone: (301) 435-0177
Fax:  (301) 435-3310
EMAIL:  William_Darby@nih.gov
Linda Stecklein
Grants Management Specialist
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 6As-49J
National Institutes of Health
Bethesda, MD  20892-6600
Telephone:  (301) 594-8847
FAX:  (301)480-3504
Email:  steckleinl@ep.niddk.nih.gov
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 Citations are No. 93.855 -
Immunology, Allergy, and Transplantation Research, No. 93.848 -
Diabetes, Endocrinology and Metabolic Diseases, No. 93.849 - Kidney,
Urologic and Hematologic Diseases, and No. 93.837 - Heart and
Vascular Diseases Research. Awards will be administered under PHS
grants policies and Federal Regulations 24 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 PHS 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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