Case series and literature review of type 1 diabetes as an alloimmune phenomenon following allogeneic hematopoietic stem cell transplantation

Case series and literature review of type 1 diabetes as an alloimmune phenomenon following allogeneic hematopoietic stem cell transplantation | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 24 May 2025 V1 Latest version Share on Case series and literature review of type 1 diabetes as an alloimmune phenomenon following allogeneic hematopoietic stem cell transplantation Authors : Elżbieta Wawrzyniak-Dzierżek [email protected] , Joanna Owoc-Lempach , Karolina Galant , Krzysztof Kalwak , and Marek Ussowicz Authors Info & Affiliations https://doi.org/10.22541/au.174807367.78987381/v1 289 views 130 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) carries the risk of immune-related complications, including rare alloimmune phenomena. Type 1 diabetes (T1D), a chronic disease marked by pancreatic beta-cell destruction, is rarely observed after allo-HSCT, and its pathogenesis in this setting remains unclear. We report two pediatric cases of T1D that developed several years after allo-HSCT for primary immunodeficiencies and review clinical and HLA data. A review of relevant literature was also conducted to put these findings in perspective. Both patients developed T1D 6.5 to 9.5 years after allo-HSCT. In both cases, pancreatic autoantibodies were detected. Neither donor had a history of autoimmune disease. Literature review suggests that post-HSCT T1D may arise through alloimmune mechanisms rather than a manifestation of graft-versus-host disease. Improving outcomes may depends on close multidisciplinary follow-up. Development of screening protocols and early detection of potential immunological processes are required. Case series and literature review of type 1 diabetes as an alloimmune phenomenon following allogeneic hematopoietic stem cell transplantation Elżbieta Wawrzyniak-Dzierżek 1 , Joanna Owoc-Lempach 1 , Karolina Galant 2 , Krzysztof Kałwak 1 , Marek Ussowicz 1 Affiliations 1 Department and Clinic of Bone Marrow Transplantation, Oncology and Pediatric Hematology, Borowska 213, 50-556 Wroclaw, Poland; 2 Department and Clinic of Pediatrics, Endocrinology, Diabetology and Metabolic Diseases, Chałubińskiego 2a, 50-368 Wrocław, Poland * Correspondence: [email protected] Key words: allogeneic hematopoietic stem cell transplantation, pediatric, type 1 diabetes Number of words in abstract: 141 Number of words in main text: 1965 Number of table: 1 Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) carries the risk of immune-related complications, including rare alloimmune phenomena. Type 1 diabetes (T1D), a chronic disease marked by pancreatic beta-cell destruction, is rarely observed after allo-HSCT, and its pathogenesis in this setting remains unclear. We report two pediatric cases of T1D that developed several years after allo-HSCT for primary immunodeficiencies and review clinical and HLA data. A review of relevant literature was also conducted to put these findings in perspective. Both patients developed T1D 6.5 to 9.5 years after allo-HSCT. In both cases, pancreatic autoantibodies were detected. Neither donor had a history of autoimmune disease. Literature review suggests that post-HSCT T1D may arise through alloimmune mechanisms rather than a manifestation of graft-versus-host disease. Improving outcomes may depends on close multidisciplinary follow-up. Development of screening protocols and early detection of potential immunological processes are required. Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for malignant and non-malignant disorders. While it offers a chance for long-term survival, it is associated with early and late autoimmune and alloimmune phenomena, which result from post-transplant immune dysregulation 1, 2,3 . The immunological mechanisms underlying these complications remain incompletely understood and may overlap with chronic graft-versus-host disease (cGvHD) 4,5 . However, not all alloimmune phenomena meet the diagnostic criteria for cGvHD, which is defined by characteristic clinical and histopathological features 6,7 . Type 1 diabetes mellitus (T1D) typically arises in genetically predisposed individuals who carry specific human leukocyte antigen (HLA) alleles, such as DR3, DR4, or B8, and is triggered by environmental or immunological insults 8 . The hallmark of T1D is the presence of pancreatic autoantibodies, including anti-glutamic acid decarboxylase (anti-GAD), islet cell antibodies (ICA), and insulinoma-associated protein-2 antibodies (IA2) 9,10 . Although T1D is not a common complication following HSCT, its incidence in transplant recipients appears to be higher than in the general population 11 . Given the potentially life-threatening nature of T1D—when presenting with diabetic ketoacidosis (DKA)—early identification of individuals at risk is critical. A few well-documented case reports and cohort studies suggest that T1D after HSCT may represent a manifestation of immune dysregulation 12 . This report presents two pediatric cases of T1D developing several years after allo-HSCT, along with a review of the existing literature. Materials and Methods This study was conducted at the Department of Pediatric Hematology, Oncology, and Bone Marrow Transplantation, Medical University of Wroclaw. A retrospective analysis was conducted using our center’s transplant database, containing clinical and follow-up data on all allo-HSCT patients. Identified cases were reviewed in detail, including transplant indication, donor characteristics, HLA typing, conditioning regimen, graft manipulation, graft-versus-host disease history, endocrine comorbidities and autoantibody testing. Donor–recipient HLA typing was analyzed for alleles associated with T1D risk. Pancreatic autoantibodies were assessed at the time of diagnosis using standard serological assays. This case series was complemented by a narrative literature review using PubMed and reference snowballing from identified articles, focusing on published case reports, registries, and cohort studies that described T1D following allo-HSCT. Relevant findings were synthesized and summarized in Table 1. Results As of the time of manuscript preparation, a total of 1,168 patients had received allo-HSCT at our institution. Of these, 806 patients were alive, and 501 had attended at least one follow-up visit within the past three years. An analysis of our database indicates that T1D occurred in 0.25% of living transplant recipients (2 cases out of 806). Patient 1 A male patient underwent HSCT at 6 months of age due to severe combined immunodeficiency (SCID T-/NK-/B+). The family history is significant for type 2 diabetes in the boy’s grandmother. The donor was his father, with a haploidentical match, and both donor and recipient shared HLA B08, DR03, DR04- alleles associated with increased susceptibility to T1D. Conditioning consisted of busulfan and fludarabine. GvHD disease prophylaxis included TCR αβ/CD19 depletion and posttransplant cyclosporine. The patient developed acute GvHD, which was successfully treated during the first post-transplant year. Immunosuppression was discontinued 15 months after transplantation. At age 10 the patient presented with classic symptoms of diabetes—polyuria, polydipsia, weight loss and anorexia. Laboratory evaluation confirmed hyperglycemia and anti-GAD antibodies. The patient was diagnosed with T1D and initiated insulin therapy. Then chimerism was mixed, it was 7% autologous. Additionally, the patient was diagnosed with hypothyroidism, and is receiving levothyroxine. Patient 2 A male patient underwent HSCT at 2.5 years of age for chronic granulomatous disease (X-linked CGD). The donor was an HLA-matched unrelated, with both donor and recipient carrying HLA B39:06, another allele associated with autoimmunity risk. The conditioning regimen included busulfan and fludarabine, and prophylaxis against rejection and GvHD consisted of alemtuzumab and cyclosporine. The patient did not develop any GvHD. At the age of 9, the patient presented with polydipsia and weight loss. He was diagnosed with T1D after biochemical workup revealed diabetic ketoacidosis, along with positive anti-GAD and anti-IA2 antibodies. He was started on insulin therapy. Then chimerism was mixed, it was 3% autologous. Additional findings include gallbladder stones on ultrasound and seasonal allergic rhinitis. The identified patients underwent stem cell transplantation due to inborn errors of immunity. None of them had cancer or had previously received chemotherapy or radiotherapy. Both patients exhibited pancreatic autoantibodies, which strongly supports an autoimmune etiology. Notably, neither donor had a history of autoimmune disease, yet both donor–recipient pairs shared HLA alleles known to confer increased susceptibility to T1D (e.g., DR03, DR04, B08, B39). Both patients are currently under the care of a pediatric diabetologist and endocrinologist. Table 1. Published case reports of T1D mellitus after allogeneic hematopoietic stem cell transplantation (Attached is an Excel file) Discussion Literature data consistently indicates that patients who undergo allo-HSCT in childhood are at a higher risk of developing type 2 diabetes (T2D) in adulthood compared to the general population 13 . In such cases, T2D often forms part of the metabolic syndrome and is associated with obesity, dyslipidemia, and insulin resistance 14 . One of the limitations of many large reports is the lack of identification of diabetes subtypes 15,16 . In contrast to T2D, T1D was rarely reported after allo-HSCT, and the epidemiological data remain sparse. Hoffmeister et al. estimated a T1D incidence of 0.52% among pediatric HSCT survivors—significantly higher than in the general pediatric population. Our institution’s data suggest a comparable incidence (0.25% among survivors, 0.40% among active follow-up), despite the small number of events. The presented cases, along with published reports, support the hypothesis that T1D post-transplantation may represent an alloimmune phenomenon 17 . In this setting, immune cells derived from the donor may initiate an autoimmune attack against the recipient’s pancreatic β-cells. In both of our patients, the timing of onset- 9.5 and 6.5 years post-transplantation- clearly separates this complication from early-onset post-transplant metabolic dysregulation such as steroid-induced hyperglycemia or new-onset diabetes after transplantation (NODAT), which typically appears within the first year and is often associated with glucocorticoid or calcineurin inhibitor exposure 18,19 . Reported cases suggest that autoimmune disorders may be transmitted from donor to recipient. However, our data and other studies show that T1D can develop even in recipients of grafts from non-diabetic donors. This suggests that alloimmunity—rather than classic autoimmunity—may be driving the process in such cases. The donor-derived T cells may recognize recipient islet antigens as foreign 20 . Lampeter et al. was the first to suggest that T1D could be transmitted from the donor to the recipient. The first report described a female patient who due to myelodysplastic syndrome underwent an allo-HSCT from her sister, who had T1D. The recipient was diagnosed with T1D 4 years after allo-HSCT 21 . In 1998, the International Bone Marrow Transplantation Registry reported 15 transplants from donors with diabetes out of 17,000 transplants, 9 of which had a confirmed diagnosis of T1D. Among the reported patients, 2 cases of T1D were recorded 22 . The presence of T1D in a donor is not sufficient to induce the disease in the recipient. Beard et al. reported a patient who underwent allo-HSCT due to aplastic anemia from a donor with T1D. After the transplant, the presence of pancreatic antibodies was confirmed, but during the 21-year follow-up, the patient did not develop diabetes 23 . Attempts to treat post-HSCT T1D with standard immunosuppression, such as cyclosporine, have shown limited efficacy. Vialettes et al. described a patient who developed T1D three years after HSCT despite prolonged immunosuppressive therapy for GvHD. High ICA levels led to a 6-month trial of cyclosporine, which failed to improve glycemic control 24 . This case suggests that post-HSCT diabetes may represent a distinct alloimmune process rather than a typical cGvHD manifestation. Matsumoto et al. reported the first case of T1D following allo-HSCT from umbilical cord blood. Anti-GAD antibodies, initially negative, but monitored due to episodes of hyperglycemia, became positive by day 38 post-transplant, before full immune reconstitution. The early onset was attributed to neonatal lymphocytes in cord blood potentially triggering autoimmunity 25 . Hoffmeister et al. analyzed 578 pediatric SCT survivors and found that 4 developed T1D 8–14 years post-transplant, with an incidence of 0.52%—notably higher than the 0.17% reported in the general U.S. pediatric population 11 . The literature also mentions other risk factors for pancreatic cell damage and, consequently, disturbances in carbohydrate metabolism. Busulfan, L-asparaginase, radiotherapy in the abdominal area, and TBI are particularly toxic to the pancreas. Prolonged glucocorticoid therapy, as well as growth hormone treatment, carry the risk of glucose intolerance disturbances lasting for several months 16,18,26 . Wędrychowicz reported a case of a girl with ALL who developed diabetes six years after allo-HSCT, following prior episodes of pancreatitis from L-asparaginase and TBI-based conditioning. Despite requiring insulin, no autoantibodies were detected. The author highlights that post-HSCT diabetes often lacks typical markers, suggesting a multifactorial origin 27 . Environmental factors, especially viral infections, can trigger T1D in genetically predisposed children. Enteroviruses, particularly Coxsackievirus B, are strongly linked to β-cell autoimmunity via molecular mimicry and direct damage. Rubella and rotavirus may also increase T1D risk 28 . Early dietary exposures—like early introduction of cow’s milk or gluten—have been investigated as T1D risk factors, though results are inconsistent. Limited breastfeeding and low vitamin D in infancy may also impair immune tolerance 29 . Changes in the gut microbiome—affected by infections, antibiotics, and diet—can disrupt mucosal immunity and promote inflammation, potentially triggering autoimmune responses 30 . According to the EBMT 2023 guidelines, regular monitoring of fasting glucose and HbA1c every 6-12 months is essential due to the heightened risk of developing type 2 diabetes, insulin resistance, and metabolic syndrome in these patients 31,32 . Given the potential severity of T1D, especially when presenting with diabetic ketoacidosis, transplant centers might consider targeted screening of high-risk patients—particularly those with HLA alleles associated with T1D or clinical features suggestive of endocrine dysfunction 33 . The mentioned guidelines do not currently advocate for routine testing for autoantibodies associated with T1D in HSCT survivors. Currently the pancreatic antibodies are only tested in first-degree relatives in the case of a diagnosis of T1D within the family 8 . Since HLA typing is already standard practice pre-HSCT, using this information post-transplant for risk stratification is feasible and cost-effective. Given the immune system’s key role in T1D, immunotherapy offers a promising treatment avenue. Teplizumab, used in early-stage T1D, significantly reduced disease onset in at-risk individuals (43% vs. 72% with placebo). Currently, it’s available only in the U.S., but shows strong potential in T1D prevention 34 . Another therapeutic approach uses regulatory T cells (Tregs), which help control immune responses. Produced ex vivo from donor blood, Tregs can be infused to suppress harmful T-cell activity. This method was first used in Poland (Gdańsk) in 10 children with early-stage T1D, leading to reduced insulin needs and lower HbA1c after two weeks 3536,37 . Other immunotherapy attempts in T1D consist of interleukin 35 (IL-35)—a cytokine that may enhance the proliferation of Treg cells, thereby promoting an immune response 38 , as well as mesenchymal stem cells, which have immunomodulatory capabilities 39 . Conclusion The cases presented in this report, alongside previously published evidence, suggest that T1D may arise as an alloimmune phenomenon rather than as a direct manifestation of cGvHD. In our experience, standard immunosuppressive strategies used for GvHD have shown no benefit in reversing or altering the course of post-transplant T1D. Early detection of T1D is crucial due to its severity and progression. Future research should focus on what triggers β-cell autoimmunity post-HSCT and identify early biomarkers, like pancreatic antibody seroconversion, for preclinical diagnosis. In light of recent advances in immunotherapy and antigen-specific tolerance induction, it is conceivable that in the future, patients developing autoimmunity post-HSCT, could benefit from tailored immunomodulatory strategies. These findings warrant broader multicenter studies to verify incidence and identify potential predictive factors. Our findings underscore the importance of close interdisciplinary collaboration between transplant specialists, endocrinologists, and diabetologists 17 . The authors declare no conflicts of interest. Generative AI disclosure During the preparation of this work the authors used OpenAI ChatGPT4o to harmonize text. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication. Source of funding : UMW statutory grant SUBZ.C200.25.080. Literature 1. Sherer Y, Shoenfeld Y. Autoimmune diseases and autoimmunity post-bone marrow transplantation. Bone Marrow Transplant . 1998;22(9):873-881. doi:10.1038/SJ.BMT.1701437 2. Yanir AD, Hanson IC, Shearer WT, et al. High Incidence of Autoimmune Disease after Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease. Published online 2018. doi:10.1016/j.bbmt.2018.03.029 3. Holbro A, Abinun M, Daikeler T. Management of autoimmune diseases after haematopoietic stem cell transplantation. Br J Haematol . 2012;157(3):281-290. doi:10.1111/j.1365-2141.2012.09070.x 4. Malard F, Mohty M. Updates in chronic graft-versus-host disease management. 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Immunol Cell Biol . 2006;84(5):413-421. doi:10.1111/J.1440-1711.2006.01458.X List of abbreviations allo-HSCT – allogeneic hematopoietic stem cell transplantation T1D – type 1 diabetes T2D – type 2 diabetes HLA – human leukocyte antigen anti-GAD – anti-glutamic acid decarboxylase antibodies ICA – islet cell antibodies IA2 – insulinoma-associated antigen-2 antibodies DKA – diabetic ketoacidosis SCID – severe combined immunodeficiency GvHD – graft-versus-host disease X-linked CGD – X-linked chronic granulomatous disease MSD – matched sibling donor ALL – acute lymphoblastic leukemia MDS – myelodysplastic syndrome NBL – Neuroblastoma AML – acute myeloid leukemia NODAT – new-onset diabetes after transplantation aGvHD – acute graft-versus-host disease cGvHD – chronic graft-versus-host disease EBMT – European Society for Blood and Marrow Transplantation HbA1c – glycated hemoglobin Supplementary Material File (t1d_cases_after_hsct.xlsx) Download 10.49 KB Information & Authors Information Version history V1 Version 1 24 May 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords bmt congenital (not hiv) endocrinology graft vs host disease immunodeficiency immunotherapy Authors Affiliations Elżbieta Wawrzyniak-Dzierżek [email protected] Department and Clinic of Bone Marrow Transplantation Oncology and Pediatric Hematology View all articles by this author Joanna Owoc-Lempach Department and Clinic of Bone Marrow Transplantation Oncology and Pediatric Hematology View all articles by this author Karolina Galant Department and Clinic of Pediatrics Endocrinology Diabetology and Metabolic Diseases View all articles by this author Krzysztof Kalwak Department and Clinic of Bone Marrow Transplantation Oncology and Pediatric Hematology View all articles by this author Marek Ussowicz Department and Clinic of Bone Marrow Transplantation Oncology and Pediatric Hematology View all articles by this author Metrics & Citations Metrics Article Usage 289 views 130 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Elżbieta Wawrzyniak-Dzierżek, Joanna Owoc-Lempach, Karolina Galant, et al. Case series and literature review of type 1 diabetes as an alloimmune phenomenon following allogeneic hematopoietic stem cell transplantation. Authorea . 24 May 2025. DOI: https://doi.org/10.22541/au.174807367.78987381/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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