Immunomodulation Followed by Antigen-Specific Treg Infusion Controls Islet Autoimmunity
| Autor: | Alexander Sands, Allison L. Bayer, Jennifer Rodriguez, Cecilia Cabello-Kindelan, Alberto Pugliese, Shane Mackey, Claudia Vazquez |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Endocrinology Diabetes and Metabolism medicine.medical_treatment Population chemical and pharmacologic phenomena 030209 endocrinology & metabolism Nod medicine.disease_cause Immune tolerance Autoimmunity 03 medical and health sciences 0302 clinical medicine Immune system Internal Medicine medicine education geography education.field_of_study geography.geographical_feature_category business.industry FOXP3 hemic and immune systems Immunosuppression Islet 030104 developmental biology Immunology business |
| Zdroj: | Diabetes. 69:215-227 |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db19-0061 |
| Popis: | Optimal immune-based therapies for type 1 diabetes (T1D) should restore self-tolerance without inducing chronic immunosuppression. CD4+Foxp3+ regulatory T cells (Tregs) are a key cell population capable of facilitating durable immune tolerance. However, clinical trials with expanded Tregs in T1D and solid-organ transplant recipients are limited by poor Treg engraftment without host manipulation. We showed that Treg engraftment and therapeutic benefit in nonautoimmune models required ablative host conditioning. Here, we evaluated Treg engraftment and therapeutic efficacy in the nonobese diabetic (NOD) mouse model of autoimmune diabetes using nonablative, combinatorial regimens involving the anti-CD3 (αCD3), cyclophosphamide (CyP), and IAC (IL-2/JES6–1) antibody complex. We demonstrate that αCD3 alone induced substantial T-cell depletion, impacting both conventional T cells (Tconv) and Tregs, subsequently followed by more rapid rebound of Tregs. Despite robust depletion of host Tconv and host Tregs, donor Tregs failed to engraft even with interleukin-2 (IL-2) support. A single dose of CyP after αCD3 depleted rebounding host Tregs and resulted in a 43-fold increase in donor Treg engraftment, yet polyclonal donor Tregs failed to reverse diabetes. However, infusion of autoantigen-specific Tregs after αCD3 alone resulted in robust Treg engraftment within the islets and induced remission in all mice. This novel combinatorial therapy promotes engraftment of autoantigen-specific donor Tregs and controls islet autoimmunity without long-term immunosuppression. |
| Databáze: | OpenAIRE |
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