Awardee OrganizationCOLUMBIA UNIVERSITY HEALTH SCIENCES
Description
Abstract Text
Project 1 Summary: The overall goal of Project 1 is to induce tolerance of porcine kidneys in
baboons by co-transplantation (Tx) of vascularized donor thymus. We have made significant progress
during the current project period (2016-2020). First, we have identified the mechanism responsible for
proteinuria, a significant obstacle in our GalT-KO pig-to-baboon kidney xenotransplant (XTx) model for
the long-term survival of life-supporting kidney xenografts, and developed effective treatment strategies
for overcoming it. Down-regulation of sphingomyelin phosphodiesterase acid-like 3b and up-regulation
of CD80 on pig podocytes were found to play critical roles in proteinuria and species incompatibility
between pig CD47 and baboon SIRPα, which caused phagocytosis of pig endothelial cells and
podocytes by baboon macrophages, was observed. We learned that either the administration of
CTLA4-Ig and rituximab mAb for GalT-KO grafts or the use hCD47 transgenic (Tg) GalT-KO kidney
grafts inhibited the development of post-transplant proteinuria, and markedly prolonged baboon survival
up to 193 days. While the exponential growth of pig grafts or drug-related side effects triggered the
euthanasia of recipient baboons, no evidence of graft rejection was seen and both pig-specific
unresponsiveness in vitro, and the development of new baboon T cells were observed in multiple
recipients VT+K XTx. Second, in collaboration with Project 2, we have achieved prolonged peripheral
blood macrochimerism lasting >60 days accompanied by gradual loss of anti-non-Gal antibodies (abs)
in baboons following hCD47+ pig intra-bone bone marrow Tx. Such durable porcine chimerism has not
been previously achieved in any primate. Our renewal is focused on achieving two aims. Aim 1:
Optimize the protocol for pig kidney XTx with vascularized thymic grafts by determining: (1)
acceptable non-Gal ab levels; (2) requirement for human complement regulatory protein Tg for recipients
with high non-Gal ab levels; (3) a strategy to prevent rejection in recipients with high non-Gal abs; (4)
acceptable preservation times of pig kidney and thymus grafts using an FDA-approved continuous
organ preservation machine; and (5) the ability to completely terminate immunosuppression. Aim 2:
Determine the ability of combined VT+KTx and IBBMTx using hCD47+ human IL3 receptor (hIL3r)
transgenic (Tg) pigs as BM donors on (achieve robust, durable T cell tolerance by combined
deletional and regulatory mechanisms. Additionally, we will also explore the ability of this
combined approach to permit long-term kidney xenograft tolerance in baboons with high non-Gal
natural antibody levels. We anticipate that the above studies will lead to achievement of the short-
term goal of extending pig VTL+KTx grafts to clinical applications in the next five years, and the long-
term goal of inducing robust tolerance of pig xenografts, respectively.
National Institute of Allergy and Infectious Diseases
CFDA Code
DUNS Number
621889815
UEI
QHF5ZZ114M72
Project Start Date
15-September-2000
Project End Date
31-December-2026
Budget Start Date
01-January-2024
Budget End Date
31-December-2024
Project Funding Information for 2024
Total Funding
$690,993
Direct Costs
$537,802
Indirect Costs
$153,191
Year
Funding IC
FY Total Cost by IC
2024
National Institute of Allergy and Infectious Diseases
$690,993
Year
Funding IC
FY Total Cost by IC
Sub Projects
No Sub Projects information available for 5P01AI045897-23 6574
Publications
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Outcomes
The Project Outcomes shown here are displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed are those of the PI and do not necessarily reflect the views of the National Institutes of Health. NIH has not endorsed the content below.
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