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NIH grant 1R01AI201182-01: Innovative Strategies to Inhibit Humoral Immunity in Renal Xenotransplantation
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Vijay Bhoj. Award: $1339047.
Start: 2026-09-18T00:00:00.
Abstract
Xenotransplantation offers extraordinary potential to address the shortage of organs for transplantation1. The
past 70 years has seen intermittent attempts to advance xenotransplantation to the clinic including work of Calne,
Reemtsma, Starzl and others who achieved modest success with concordant kidneys and livers2–4. However,
attempts at discordant pig organ use was ultimately met with concerns of xeno-zoonoses and poor outcomes
associated with xenoimmunity5,6. Following the CRISPR revolution, the xeno-field has matured to take center
stage in transplantation raising hope for an unlimited pool of life-saving organs7,8. To date, a handful of porcine
heart and kidney grafts have been transplanted to decedent humans with encouraging short-term outcomes8–11.
Even more compelling are the cases of xenotransplants in living patients, with the longest surviving12 >8 months
with the others generally lost to residual antibody mediated injury. In parallel, rigorous NHP studies of renal
xenotransplants carrying multiple gene edits by eGenesis found that, like the human cases, AMR and CAMR (and
TMA) represent major remaining impediments to success 13. To surmount this recalcitrant barrier, we will utilize
CART cells to achieve deep depletion of B lymphocytes (and plasma cells if needed) to address the incomplete
inhibition of humoral immunity in xenotransplantation to date.
The novel capability of CART cells to achieve profound B cell depletion to ameliorate the humoral immune
response in xenotransplantation also offers a unique parallel opportunity to explore the immunological
consequences of such depletion on both graft survival and the consequences to the nascent immunological
repertoire; specifically, we seek to understand the impact of an immune reset on the B cell pool and its associated
impact on B and T cell based Xeno immunity. We hypothesize that such a reset, if the B cell repertoire remains
immature, may facilitate immune unresponsiveness to the graft. This idea is founded on a series of studies in mice,
NHP and humans (detailed below) that accompany countless studies in autoimmunity, revealing that a reset of
the B cell repertoire by B cell ablation can foster a pro-survival milieu. Our mechanistic studies demonstrate residual
tissue resident B cells and plasma cells were not effectively eliminated by Rituxan. We believe this incomplete B
cell depletion explains the poor survival of porcine renal xenografts in NHP and humans14–16 and posit that robust
B cell ablation and repopulation by a nascent-immature pool has the potential to promote renal xenograft survival.
Parallel studies already underway in the allo-setting with Cyno NHP (Naji et al) will offer a fascinating comparator
for the studies proposed herein. Finally, we develop and apply an mRNA-LNP based method of In Vivo CAR T
generation to facilitate clinical translation. In summary, this proposal is founded on compelling preliminary data,
offers novel hypotheses, adds new therapeutics and innovative technologies to the NHP model, with the ultimate
goal of providing a stronger base for later clinical application. As best we are aware, these studies are novel and we
believe they have the potential to significantly advance renal xenotransplant outcomes.document fetched 2026-09-27 02:45