Curing autoimmune diabetes in mice with islet and hematopoietic cell transplantation after CD117 antibody-based conditioning
Preksha Bhagchandani, Stephan A. Ramos, Bianca Rodriguez, Xueying Gu, Shiva Pathak, Yuqi Zhou, Yujin Moon, Nadia Nourin, Charles A. Chang, Jessica Poyser, Brenda J. Velasco, Weichen Zhao, Hye-Sook Kwon, Richard Rodriguez, Diego M. Burgos, Mario A. Miranda, Everett Meyer, Judith A. Shizuru, Seung K. Kim
Preksha Bhagchandani, Stephan A. Ramos, Bianca Rodriguez, Xueying Gu, Shiva Pathak, Yuqi Zhou, Yujin Moon, Nadia Nourin, Charles A. Chang, Jessica Poyser, Brenda J. Velasco, Weichen Zhao, Hye-Sook Kwon, Richard Rodriguez, Diego M. Burgos, Mario A. Miranda, Everett Meyer, Judith A. Shizuru, Seung K. Kim
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Research Article Autoimmunity Endocrinology

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

Abstract

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 nontoxic bone marrow conditioning protocols is needed to expand clinical use. We developed a chemotherapy-free, nonmyeloablative (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–CD117 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 third-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.

Authors

Preksha Bhagchandani, Stephan A. Ramos, Bianca Rodriguez, Xueying Gu, Shiva Pathak, Yuqi Zhou, Yujin Moon, Nadia Nourin, Charles A. Chang, Jessica Poyser, Brenda J. Velasco, Weichen Zhao, Hye-Sook Kwon, Richard Rodriguez, Diego M. Burgos, Mario A. Miranda, Everett Meyer, Judith A. Shizuru, Seung K. Kim

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Figure 1

Nonmyeloablative conditioning promotes robust and durable allogeneic donor chimerism in a radioresistant NOD model.

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Nonmyeloablative conditioning promotes robust and durable allogeneic don...
(A) Transplantation schematic and strains used. (B) Reduced intensity conditioning regimen. (C) Chimerism analysis of peripheral blood 4 weeks after conditioning and HCT, depicting overall, CD3+ T cell, CD19+ B cell, CD11b+ myeloid cell, and CD49b+ NK cell donor (CD45.2+) chimerism (n = 15, sum of 3 independent experiments). (D) Longitudinal chimerism analysis of peripheral blood over a 20-week period (n = 15; sum of 3 independent experiments). (E) Chimerism analysis of host spleen at 20 weeks after HCT (n = 15, sum of 3 independent experiments). (F) Chimerism analysis of host bone marrow at 20 weeks after HCT, including Lin–Sca1+cKit+ (LSK) HSCs (n = 15, sum of 3 independent experiments). (C–F) Data are represented as mean ± SEM. XRT, radiation therapy; HCT, hematopoietic cell transplant; BTB, baricitinib; TCD, T cell depletion.