| Summary: | 碩士 === 國防醫學院 === 微生物及免疫學研究所 === 101 === The differential activation of T helper (Th) cells and production of cytokines contribute to graft rejection or tolerance. In general, the Th1−type cytokines and cytotoxic T cells are detected consistently in host undergoing rejection, whereas Th2 and regulatory T cells (Treg) responses are linked to a tolerance condition. Recently, the role of Th cell subsets in graft rejection has been further discussed after the thorough characterization of the pro-inflammatory Th17 cells. Several evidences have demonstrated that Th17 cells and Th17-related cytokines have the capacity to cause the rejection of cardiac or skin allograft in the absence of Th1 cells. However, the conclusion obtained by using IFN-γ knockout, IL-17 knockout or T-bet knockout mice as recipients and neutralizing Th17-related cytokines (IL-6 and IL-17) in wild type recipients in different transplantation models did not clarify the contribution of each T cell subsets in the graft rejection. This is probably because some cytokines are double-edged swords for pro-inflammatory and anti-inflammatory properties depending on the timing and selective cell types that release them. Altogether, it is not clear whether Th1 and Th17 cells work redundantly or synergistically to cause graft rejection.
In recipients, dendritic cells (DC) uptake the donor antigens and present them to the T cells which promote different types of effector or regulatory T cells depending on their status of maturation and the profile of cytokines they secrete. IL-12 family cytokines IL-12, IL-23 and IL-27 are mainly secreted by DC and play crucial roles in the dendritic cell-driven T cell differentiation. Besides, engagement of Toll-like receptors (TLRs) by endogenous ligands or by microbial products in the transplantation procedure promotes DC activation and leads to the production of cytokines responsible for the polarization of T cells. Thus, DC may become a primary target to fundamentally investigate the T cell activation and differentiation in recipients.
To determine the differential effects of IL-12 family cytokines in DC-driven T cell differentiation in vitro, we co-cultured bone marrow-derived dendritic cells (BMDCs) from IL-12p35 knockout, IL-23p19 knockdown or IL-27p28 knockdown NOD mice with NOD/BDC2.5 TCR transgenic CD4+ T cells in the presence of specific peptide to determine the modulatory effects of the IL-12 family cytokines on the functions of antigen-specific T cells, in terms of activation, proliferation, cytokine production and differentiation. In these results, we found that BMDCs from IL-12p35 knockout, IL-23p19 knockdown or IL-27p28 knockdown mice displayed similar capacity to induce T cell proliferation. However, BMDCs from IL-12p35 knockout or IL-23p19 knockdown mice showed moderately reduced ability to promote Th1 and Th17 differentiation. In contrast, BMDCs from IL-27p28 knockdown mice displayed no effects on Th1 and Th17 development.
To further explore the Th cell responses in islet graft rejection or tolerance, we transplanted islets into streptozotocin-induced diabetic NOD/SCID recipients with IL-12p35 knockout, IL-23p19 knockdown or IL-27p28 knockdown background. The normoglycemic recipients were then received diabetic CD4+ T cells and blood glucose was monitored daily. The histology of islet grafts and the differential Th cell subsets were analyzed at the end of the study. Our results showed that the survival of islet grafts was prolonged in IL-12p35 knockout and IL-23p19 knockdown recipients, respectively, as compared with the control recipients.
These data indicate that IL-12 family cytokines play important roles in controlling Th cell differentiation and subsequent islet graft rejection or tolerance. Our data reveal that IL-12 or IL-23 promotes the detrimental Th1 and Th17 responses respectively, subsequently mediating the islet grafts rejection. Thus, blockade of IL-12 or IL-23 may act as an attractive and therapeutic target to reduce the magnitude of the rejection response. Furthermore, these animal models can be further applied to study other types of transplants (e.g., skin and heart) and dissect the role of Th cell subsets in the rejection response.
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