Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+ CD25+ FoxP3+ T cells
| Autor: | Louis Boon, Hans J. P. M. Koenen, J J A Coenen, E. van Rijssen, Luuk B. Hilbrands, Ahmad Kasran, Irma Joosten |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Interleukin 2
Regulatory T cell Graft vs Host Disease chemical and pharmacologic phenomena Thymus Gland T-Lymphocytes Regulatory Auto-immunity transplantation and immunotherapy [N4i 4] Immune tolerance Mice Immune system Immune Regulation [NCMLS 2] Interventional oncology [UMCN 1.5] immune system diseases Immune Tolerance Animals Homeostasis Medicine IL-2 receptor Sirolimus Peripheral tolerance induction Mice Inbred BALB C Mice Inbred C3H Transplantation business.industry FOXP3 Forkhead Transcription Factors hemic and immune systems Hematology Renal disorders [UMCN 5.4] Disease Models Animal medicine.anatomical_structure surgical procedures operative Immunology Cyclosporine Cancer research Interleukin-2 business Immunosuppressive Agents Signal Transduction medicine.drug |
| Zdroj: | Bone Marrow Transplantation, 39, 537-45 Bone Marrow Transplantation, 39, 9, pp. 537-45 |
| ISSN: | 0268-3369 |
| Popis: | Contains fulltext : 52757.pdf (Publisher’s version ) (Closed access) Graft-versus-host-disease (GVHD) is the most common cause of poor outcome after allogeneic stem cell transplantation (SCT). Of late, exploitation of FOXP3(+) regulatory T-cell (T(REG)) function is emerging as a promising strategy in suppression of GVHD, while preserving graft-versus-leukemia (GVL). Cyclosporine and rapamycin reduce the expansion of effector T cells by blocking interleukin (IL)-2, but signaling by IL-2 is pivotal for T(REG) homeostasis. The resolution of GVHD is critically dependent on thymus-dependent reconstitution of the immunoregulatory system. Thus, there has been concern about the impact of blocking IL-2 signaling by immunosuppressive agents on T(REG) homeostasis. Here we demonstrate in a mouse model that in contrast to rapamycin, cyclosporine compromises not only the thymic generation of CD4(+)CD25(+)FoxP3(+) T cells but also their homeostatic behavior in peripheral immune compartments. Treatment with cyclosporine resulted in a sharp reduction of peripheral CD25(+)FoxP3(+) T cells in all immune compartments studied. Prolonged rapamycin treatment allowed for thymic generation of CD4(+)FoxP3(+) T cells, whereas treatment with cyclosporine led to a reduced generation of these cells. In conclusion, cyclosporine and rapamycin differentially affect homeostasis of CD4(+)FoxP3(+) T(REG) in vivo. As peripheral tolerance induction is a prerequisite for successful treatment outcome after allogeneic SCT, these findings are of potential clinical relevance. |
| Databáze: | OpenAIRE |
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