Ex Vivo Expanded Human Regulatory T Cells Can Prolong Survival of a Human Islet Allograft in a Humanized Mouse Model
| Autor: | Derek W. R. Gray, Kathryn J. Wood, Paul Johnson, Piotr Trzonkowski, Satish N. Nadig, Stephen J. Hughes, W Zhang, Douglas C. Wu, Joanna Hester |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Graft Rejection
Adoptive cell transfer Cellular differentiation medicine.medical_treatment Transplantation Heterologous Humanized mouse model Cellular therapy Islets of Langerhans Transplantation chemical and pharmacologic phenomena Biology T-Lymphocytes Regulatory Diabetes Mellitus Experimental Interferon-gamma Mice 03 medical and health sciences 0302 clinical medicine Allograft medicine Animals Humans Transplantation Homologous Basic and Experimental Research Interferon gamma Islet transplantation 030304 developmental biology Mice Knockout Mice Inbred BALB C 0303 health sciences Transplantation geography geography.geographical_feature_category Graft Survival Cell Differentiation hemic and immune systems Immunosuppression Regulatory T cells Islet Adoptive Transfer 3. Good health DNA-Binding Proteins Disease Models Animal Immunology Humanized mouse Ex vivo Signal Transduction 030215 immunology medicine.drug |
| Zdroj: | Transplantation |
| ISSN: | 0041-1337 |
| DOI: | 10.1097/tp.0b013e31829fa271 |
| Popis: | Background Human regulatory T cells (Treg) offer an attractive adjunctive therapy to reduce current reliance on lifelong, nonspecific immunosuppression after transplantation. Here, we evaluated the ability of ex vivo expanded human Treg to prevent the rejection of islets of Langerhans in a humanized mouse model and examined the mechanisms involved. Methods We engrafted human pancreatic islets of Langerhans into the renal subcapsular space of immunodeficient BALB/c.rag2−/−.cγ−/− mice, previously rendered diabetic via injection of the β-cell toxin streptozocin. After the establishment of stable euglycemia, mice were reconstituted with allogeneic human peripheral blood mononuclear cells (PBMC) and the resultant alloreactive response studied. Ex vivo expanded CD25highCD4+ human Treg, which expressed FoxP3, CTLA-4, and CD62L and remained CD127low, were then cotransferred together with human PBMC and islet allografts and monitored for evidence of rejection. Results Human islets transplanted into diabetic immunodeficient mice reversed diabetes but were rejected rapidly after the mice were reconstituted with allogeneic human PBMC. Cotransfer of purified, ex vivo expanded human Treg prolonged islet allograft survival resulting in the accumulation of Treg in the peripheral lymphoid tissue and suppression of proliferation and interferon-γ production by T cells. In vitro, Treg suppressed activation of signal transducers and activators of transcription and inhibited the effector differentiation of responder T cells. Conclusions Ex vivo expanded Treg retain regulatory activity in vivo, can protect a human islet allograft from rejection by suppressing signal transducers and activators of transcription activation and inhibiting T-cell differentiation, and have clinical potential as an adjunctive cellular therapy. Supplemental digital content is available in the article. |
| Databáze: | OpenAIRE |
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