Islets co-engineered with thrombomodulin and CD47 achieve sustained survival in allogeneic recipients without chronic immunosuppression
Shadab Kazmi, Mohammad Tarique, Darshan Badal, Vahap Ulker, Ali Turan, Kathleen M. Yee-Flores, Abdalmonam Jadou Nejma, Esma S. Yolcu, Haval Shirwan
Shadab Kazmi, Mohammad Tarique, Darshan Badal, Vahap Ulker, Ali Turan, Kathleen M. Yee-Flores, Abdalmonam Jadou Nejma, Esma S. Yolcu, Haval Shirwan
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Research Article Immunology

Islets co-engineered with thrombomodulin and CD47 achieve sustained survival in allogeneic recipients without chronic immunosuppression

Abstract

Allogeneic islet transplantation is an effective treatment for type 1 diabetes, but its clinical use is limited by rejection involving innate and adaptive immune responses, requiring lifelong immunosuppression. We herein engineered islets that transiently display 2 immunomodulators chimeric with streptavidin (SA), thrombomodulin (SA-TM) and CD47 (SA-CD47), for localized modulation of both innate and adaptive immune responses. The engineering process did not impact islet viability, glucose responsiveness, and metabolic activity. Intraportal transplantation into allogeneic recipients achieved sustained survival, with 8 out of 11 grafts surviving 120–330 days without immunosuppression. In contrast, non-engineered islets were acutely rejected (median survival time [MST] = 12 days), while islets engineered with SA-TM showed delayed rejection (MST = 13.5 days) and those with SA-CD47 exhibited prolonged survival (MST = 24 days). Double-engineered islets generated a localized tolerogenic immune environment characterized by low frequencies of inflammatory innate immune cells and increased frequencies of M2 macrophages, myeloid-derived suppressor cells, and CD4+FoxP3+ T regulatory cells. The transcriptomic analysis showed downregulation of proinflammatory and upregulation of immune regulatory pathways. Our results demonstrate that transient co-display of immunomodulatory molecules on the islet surface is a versatile platform with significant translational potential for islet transplantation.

Authors

Shadab Kazmi, Mohammad Tarique, Darshan Badal, Vahap Ulker, Ali Turan, Kathleen M. Yee-Flores, Abdalmonam Jadou Nejma, Esma S. Yolcu, Haval Shirwan

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Figure 2

Islets engineered to transiently co-display SA-TM and SA-CD47 proteins on their surface achieve long-term survival in diabetic allogeneic recipients.

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Islets engineered to transiently co-display SA-TM and SA-CD47 proteins o...
BALB/c islets were engineered with individual or a combination of SA-TM and SA-CD47 proteins, and 700 IEQ were transplanted intraportally into streptozotocin-induced diabetic C57BL/6 recipients. Naive (unmodified islets) were used as controls. Recipients were monitored for blood glucose levels, and those exceeding 250 mg/dL on 2 consecutive days were considered rejected. (A) Graft survival. **P < 0.01; ***P < 0.001 by log-rank (Mantel-Cox) test. (B) Non-fasting blood glucose levels (BGL) of the indicated graft recipients. (C) IPGTT was performed on long-term recipients of islets engineered with SA-CD47 (n = 2; 52 and 108 days after transplantation) and SA-CD47/TM (n = 1, 126 days; n = 5, > 226 days after transplantation), with naive mice without transplant serving as controls. (D) The area under the curve (AUC) was calculated for the data presented in C. Tx, transplantation. Data are presented as mean ± SD. ***P < 0.001 by unpaired, 2-tailed Student’s t test.