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JAK Inhibitor as a Novel Conditioning Approach to Establish Mixed Chimerism and Prevent Type 1 Diabetes Nonmyeloablatively

H. Xu1, A. Merchak1, J. Xu2, Y. Huang1, S. T. Ildstad1

1University of Louisville, Institute for Cellular Therapeutics, Louisville, KY, 2DuPont Manual High School, Louisville, KY

Meeting: 2019 American Transplant Congress

Abstract number: A43

Keywords: Autoimmunity, Bone marrow transplantation, Jak/STAT, Mice

Session Information

Session Name: Poster Session A: B-cell / Antibody /Autoimmunity

Session Type: Poster Session

Date: Saturday, June 1, 2019

Session Time: 5:30pm-7:30pm

 Presentation Time: 5:30pm-7:30pm

Location: Hall C & D

*Purpose: Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of islet β cells. T1D has been found to be associated with defects in the hematopoietic stem cells. Successful bone marrow transplantation (BMT) interrupts disease progression and halts autoimmune disease progression. We previously demonstrated that by targeting recipient immune cells (T, NK cells and macrophages) total body irradiation (TBI) can be reduced to safe and clinically acceptable levels in a mouse BMT model. Here, we hypothesized that JAK/STAT immune signaling pathways may be novel targets for establishing chimerism as an alternative to immune cell depletion. The JAK/STAT pathway serves a fundamental role in regulation of cell activation and differentiation by transducing signals from extracellular cytokines to their transmembrane receptors, and then to the nucleus.

*Methods: Non-obese diabetic (NOD) mice are commonly used as an animal model for spontaneous T1D. NOD (MHC-H2d) mice were conditioned with 300 to 100 cGy TBI (day 0) and cyclophosphamide (CyP, day +2) in combination with JAK inhibitors [tofacitinib (Tofa), day 0 to +4]. 30×106 bone marrow cells from MHC-disparate B6 (H2b) mice were transplanted on day 0.

*Results: At 1 month post BMT, 100% of NOD mice engrafted with 300cGy/CyP/Tofa at 65.71 ± 5.59% average levels of donor chimerism, which was significantly higher than the average level of donor chimerism in mice that received 300cGy/CyP (17.07 ± 4.50%, p < 0.00001). With 200 and 100cGy TBI plus Tofa/CyP, 100% of NOD mice engrafted with donor chimerism at 49.1 ± 7.6% and 21.3 ± 11.2% at 1 month, respectively. The donor BMC engraftment was durable. Engrafted animals exhibited multilineage cell production, including donor T, B, NK cells, macrophages, and granulocytes. CD4–CD8– double negative (DN) thymocytes in NOD mice were reported to be partially blocked at the DN1 (CD44+CD25–) to DN2 (CD44+CD25+) transition. This defect of T cell development in the NOD thymus was not found to be corrected after BMT from the disease-resistant donors, suggesting that the defect was from the T progenitor cells. Moreover, none of the chimeric NOD mice developed T1D.

*Conclusions: Targeting JAK3/1/2 with Tofa can decrease the TBI dose sufficient for establishing chimerism to a minimum and prevent T1D. These findings may have a significant impact on the development of novel immune-based conditioning strategies for T1D-prevention.

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To cite this abstract in AMA style:

Xu H, Merchak A, Xu J, Huang Y, Ildstad ST. JAK Inhibitor as a Novel Conditioning Approach to Establish Mixed Chimerism and Prevent Type 1 Diabetes Nonmyeloablatively [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/jak-inhibitor-as-a-novel-conditioning-approach-to-establish-mixed-chimerism-and-prevent-type-1-diabetes-nonmyeloablatively/. Accessed May 30, 2025.

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