Preventing graft re-JAK-tion: safer transplant conditioning enables murine islet allograft tolerance and diabetes reversal
Stephen P. Persaud, John F. DiPersio
Stephen P. Persaud, John F. DiPersio
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Commentary

Preventing graft re-JAK-tion: safer transplant conditioning enables murine islet allograft tolerance and diabetes reversal

Abstract

Transplantation of allogeneic islets of Langerhans, which include the insulin-producing β cells of the endocrine pancreas, holds curative potential for type 1 diabetes (T1D). However, protecting the allograft from the host immune system has long been a challenge impeding wider use of this therapy. Inducing mixed hematopoietic chimerism via allogeneic hematopoietic stem cell transplantation (HSCT) can achieve long-lasting donor-specific immune tolerance, but the toxicities of conventional HSCT conditioning agents limit the use of this approach. In this issue of the JCI, Bhagchandani et al. have used the JAK1/2 inhibitor baricitinib to optimize a nonmyeloablative antibody-based HSCT conditioning regimen, achieving multilineage hematopoietic engraftment, which enabled curative islet allotransplantation in a mouse model of T1D.

Authors

Stephen P. Persaud, John F. DiPersio

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Figure 1

Exploring JAK1/2 inhibition as a single-agent immunosuppression regimen to enable allo-HSCT and subsequent islet transplantation.

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Exploring JAK1/2 inhibition as a single-agent immunosuppression regimen ...
Bhagchandani et al. (16) showed that adding subcutaneous injections of the JAK1/2 inhibitor baricitinib to an allo-HSCT– and anti-CD117–based preconditioning regimen enabled successful pancreatic islet transplantation and diabetes reversal in the NOD mouse model of spontaneous autoimmune diabetes. In previous studies, JAK1/2 inhibition with oral ruxolitinib alone overcame T cell– and NK cell–mediated rejection to enable fully mismatched allo-HSCT when combined with CD45- and CD117-targeted ADCs (4). This suggests that JAK1/2 inhibition alone may enable TBI-free allo-HSCT in the NOD mouse model that then allows for curative islet transplantation and diabetes reversal. The mechanisms by which JAK1/2 inhibitors prevented T cell–mediated rejection remain incompletely defined. Notably, in prior work, a short peritransplant course of JAK1/2 inhibition enabled the HSC allograft to persist months after the drug was stopped, suggesting effective induction of peripheral and central tolerance that prevented residual host T cells or de novo–generated T cells, respectively, from depleting allogeneic HSCs or their progeny (4, 10).