Biology subjects

Bhagchandani, P.

Publications and source records attributed to Bhagchandani, P..

4 recordsLinked to original sources

bioRxiv2025

Curing autoimmune diabetes with islet and hematopoietic cell transplantation after CD117 antibody-based conditioning

Mixed hematopoietic chimerism after allogeneic hematopoietic cell transplantation (HCT) promotes tolerance of transplanted donor-matched solid organs, corrects autoimmunity, and could transform therapeutic strategies for autoimmune type 1 diabetes (T1D). However, development of non-toxic bone marrow conditioning protocols is needed to expand clinical use. We developed a chemotherapy-free, non-myeloablative (NMA) conditioning regimen that achieves mixed chimerism and allograft tolerance across MHC barriers in NOD mice. We obtained durable mixed hematopoietic chimerism in prediabetic NOD mice using anti-c-Kit monoclonal antibody, T-cell depleting antibodies, JAK1/2 inhibition, and low-dose total body irradiation prior to transplantation of MHC-mismatched B6 hematopoietic cells, preventing diabetes in 100% of chimeric NOD:B6 mice. In overtly diabetic NOD mice, NMA conditioning followed by combined B6 HCT and islet transplantation durably corrected diabetes in 100% of chimeric mice without chronic immunosuppression or graft-versus-host disease (GVHD). Chimeric mice remained immunocompetent, as assessed by blood count recovery and rejection of 3rd party allogeneic islets. Adoptive transfer studies and analysis of autoreactive T cells confirmed correction of autoimmunity. Analysis of chimeric NOD mice revealed central thymic deletion and peripheral tolerance mechanisms. Thus, with NMA conditioning and cell transplantation, we achieved durable hematopoietic chimerism without GVHD, promoted islet allograft tolerance, and reversed established T1D. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=197 SRC="FIGDIR/small/673576v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@23fcdorg.highwire.dtl.DTLVardef@1aac97borg.highwire.dtl.DTLVardef@191e06forg.highwire.dtl.DTLVardef@25be2b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Improved conditioning for hematopoietic chimerism induces islet tolerance to cure diabetes

Mixed hematopoietic chimerism after hematopoietic cell transplantation (HCT) can modulate the immune system and induce tolerance to allogeneic tissues. However, bone marrow conditioning-related toxicities preclude wider adoption of HCT for transplant allotolerance. We sought agents that reduced conditioning intensity, while promoting durable mixed chimerism after HCT across complete major histocompatibility complex (MHC) mismatch in diabetic mice, permitting islet allotransplantation and diabetes reversal. We systematically tested baricitinib (JAK1/2 inhibitor), venetoclax (Bcl2 inhibitor), and CD47 antibody, agents in current clinical use, and quantified hematopoietic chimerism after HCT. Combined with CD117 antibody, transient T cell depletion, and just 10 centigray (cGy) total body irradiation (TBI), these agents enabled durable mixed chimerism and matching allo-islet tolerance, to cure diabetes without evidence of GVHD. Thus, we have developed a conditioning regimen to promote allogeneic mixed hematopoietic chimerism and transplanted islet allotolerance that minimizes conditioning radiation and cures diabetes, a significant achievement.

immunology↗

bioRxiv2021

Islet transplantation tolerance in animals with defined histocompatibility and diabetes

Advances in organ transplantation benefit from development of genetically inbred animal strains with defined histocompatibility and cell-specific markers to distinguish donor and host cell subsets. For studies of pancreatic islet transplantation tolerance in diabetes, an invariant method to ablate host {beta} cells and induce diabetes would provide an immense additional advantage. Here we detail development and use of B6 RIP-DTR mice, an immunocompetent line permitting diabetes induction with 100% penetrance. This inbred line is homozygous for the C57BL/6J major histocompatibility complex (MHC) haplotype and expresses the mutant CD45.1 allele in the hematopoietic lineage. {beta} cell-specific expression of a high-affinity receptor for diphtheria toxin (DT) permits experimental {beta} cell ablation and diabetes induction after DT administration. Diabetes reversal for over one year was achieved after transplantation with congenic C57BL/6J islets, but not with MHC-mismatched BALB/c islets, which were rapidly rejected. In summary, the generation of a C57BL/6J congenic line harboring the CD45.1 allele and Ins2-HBEGF transgene should advance studies of islet transplantation tolerance and mechanisms to improve islet engraftment and function, thereby optimizing development of cell replacement strategies for diabetes mellitus.

immunology↗

bioRxiv2020

Antigen-specific induction of CD4+CD8αα+ intraepithelial T lymphocytes byBacteroidetes species

The microbiome contributes to the development and maturation of the immune system1-3 In response to commensal bacteria, CD4+ T cells can differentiate into distinct functional subtypes with regulatory or effector functions along the intestine. Peripherally-induced Foxp3+-regulatory T cells (pTregs) maintain immune homeostasis at the intestinal mucosa by regulating effector T cell responses against dietary antigens and microbes4. Similarly to pTregs, a subset of small intestine intraepithelial lymphocytes CD4+CD8+ (CD4IELS) exhibit regulatory properties and promote tolerance against dietary antigens5. Development of CD4IELS from conventional CD4+ T cells or from Treg precursors depends on the microbiota5,6. However, the identity of the microbial antigens recognized by CD4IELs remains unknown. We identified species belonging to the Bacteroidetes phylum as commensal bacteria capable of generating CD4IEL from naive CD4+ T cells expressing the pTreg transnuclear (TN) monoclonal TCR6 as well as from polyclonal WT T cells. We found that {beta}-hexosaminidase, a widely conserved carbohydrate-metabolizing enzyme in the Bacteroidetes phylum, is recognized by TN T cells, which share their TCR specificity with CD4+ T cells found in the intraepithelial compartment of polyclonal specific-pathogen-free (SPF) mice. In a mouse model of colitis, {beta}-hexosaminidase-specific CD4IELs provided protection from ulceration of the colon and weight loss. Thus, a single T cell clone can recognize a variety of abundant commensal bacteria and elicit a regulatory immune response at the intestinal epithelial surface.

immunology↗