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This commentary discusses how inducing mixed hematopoietic chimerism through HSCT can promote long-lasting donor-specific tolerance, but also highlights the barriers imposed by chemotherapy/irradiation. It focuses on using the JAK1/2 inhibitor baricitinib within a nonmyeloablative, antibody-based conditioning strategy to support multilineage engraftment, enable curative islet allotransplantation in a murine model, and achieve diabetes reversal, while addressing risks of systemic immunosuppression.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/preventing-graft-re-jak-tion-safer-transplant-conditioning-enables-murine-islet-allograft-tolerance-and-diabetes-reversal/413895/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/preventing-graft-re-jak-tion-safer-transplant-conditioning-enables-murine-islet-allograft-tolerance-and-diabetes-reversal/413895.png","ImageObject",300,407,{"name":92,"@type":93},"Patrick","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-28",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is immune tolerance important for allogeneic islet transplantation in type 1 diabetes?","Question",{"text":112,"@type":113},"Immune rejection remains a major hurdle to successful transplantation. Long-lasting donor-specific immune tolerance can protect the graft and reduce reliance on prolonged immunosuppression.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What limitation of conventional allo-HSCT conditioning restricts its wider use?",{"text":117,"@type":113},"Conventional conditioning agents carry toxicities from chemotherapy and/or irradiation. These treatment-related adverse events can limit eligibility, especially in elderly or infirm patients.",{"name":119,"@type":110,"acceptedAnswer":120},"How does baricitinib improve transplant conditioning in the described mouse model?",{"text":121,"@type":113},"The commentary explains that adding subcutaneous 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.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},413895,1790875500,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":19,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":52,"preview_page_count":4},549758146520,"https://ap-avatar.wpscdn.com/avatar/80002397d8c0411e94?_k=1775819394049821470","The Journal of Clinical Investigation COMMENTARY  \nPreventing graft re-JAK-tion: safer transplant conditioning enables murine islet allograft tolerance and diabetes reversal  \nStephen P. Persaud1 and John F. DiPersio2  \n1Division of Laboratory and Genomic Medicine, Department of Pathology & Immunology, and 2Section of Cellular Therapy, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.  \nTransplantation of allogeneic islets of Langerhans, which include the insulinproducing 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 ofT1D.  \nHuman islet pancreatic transplantation, first described in 1989 by Scharp, Lacy, and colleagues (1), has the potential to cure T1D and eliminate affected individuals’ lifelong need for insulin therapy. However, islet rejection remains a major hurdle to successful transplantation, necessitating longterm immunosuppression. Adding further complication, the drugs that suppress islet rejection can be toxic to β cells and increase risk of cancer and infection (2) . The serious adverse effects of systemic immunosuppression regimens have motivated development of alternative strategies that promote durable immune tolerance in transplant recipients.  \nAllogeneic HSCT for tolerance induction  \nAllogeneic HSCT (allo-HSCT) holds vast  \ntherapeutic potential for numerous diseases of the blood and immune system. Moreover, allo-HSCT before solid organ transplantation (SOT) can engraft the immune system of the donor into the recipient, resulting in stable mixed-donor chimerism that enables a lasting state of tolerance to the transplanted organ. However, the potential benefits of allo-HSCT must be weighed against the treatment-related toxicities caused by the chemotherapy and/or irradiation that are conventionally used as transplant conditioning agents. Indeed, the potential for severe adverse events resulting from HSCT conditioning may partially explain why allo-HSCT is typically reserved for the most life-threatening clinical indications, such as acute myeloid leukemia (AML) and other  \nRelated Article: [https://doi.org/10.1172/JCI190034](https://doi.org/10.1172/JCI190034)  \nConflict of interest: JFD receives research funding from Wugen and NeoImmuneTech, has equity ownership in Magenta Therapeutics and Wugen, and consults for Vertex, BlueBird Bio, and Incyte. SPP and JFD hold a patent (USPTO 17/504,656) for the combination of antibody-drug conjugates with Janus kinase inhibitors for allogeneic stem cell transplant conditioning.  \nCopyright: © 2026, Persaud et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.  \nReference information: J Clin Invest. 2026;136(1):e201105 . [https://doi.org/10.1172/JCI201105](https://doi.org/10.1172/JCI201105) .  \nhematologic malignancies. However, in elderly or infirm patients for whom alloHSCT may be otherwise indicated, the risk of adverse treatment-related events might preclude them from being candidates for this potentially lifesaving therapy altogether. Therefore, overcoming the barriers to safe and effective allo-HSCT imposed by conditioning-related toxicities would broaden the patient populationsand clinical indications in which transplantation may safely be used, inc","cbCaigPql8OG6sLa","https://ap.wps.com/l/cbCaigPql8OG6sLa","pdf",249951,"English","# Preventing graft re-JAK-tion\n## Islet transplantation challenges and tolerance induction\n## Allogeneic HSCT as a tolerance strategy\n## Minimally toxic, antibody-based conditioning\n## JAK1/2 inhibition to enable allo-HSCT and islet transplantation","[{\"question\":\"Why is immune tolerance important for allogeneic islet transplantation in type 1 diabetes?\",\"answer\":\"Immune rejection remains a major hurdle to successful transplantation. Long-lasting donor-specific immune tolerance can protect the graft and reduce reliance on prolonged immunosuppression.\"},{\"question\":\"What limitation of conventional allo-HSCT conditioning restricts its wider use?\",\"answer\":\"Conventional conditioning agents carry toxicities from chemotherapy and/or irradiation. These treatment-related adverse events can limit eligibility, especially in elderly or infirm patients.\"},{\"question\":\"How does baricitinib improve transplant conditioning in the described mouse model?\",\"answer\":\"The commentary explains that adding subcutaneous 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.\"}]","Preventing graft re-JAK-tion: safer transplant conditioning enables murine islet allograft tolerance and diabetes reversal | PDF",1790596126]