Abstract
Abstract 308
Graft-vs-host disease (GVHD) is an alloimmune response after allogeneic hematopoietic stem transplantation (HSCT) mediated by donor T cells against antigen presented by recipient dendritic cells. Our studies with a murine model of GVHD indicate that the complement system regulates the alloimmune response leading to acute GVHD.
We used the disparity in MHC class I and II antigens between BALB/c (H-2d) as donors and either wild-type (WT) or complement deficient C57BL/6 (H-2b) as recipients. We found that mice deficient in the central component of the complement system (C3−/−) had significantly lower GVHD-related mortality and morbidity compared to WT recipient mice. Within 8 weeks after BMT, 80% of WT recipient mice and only 25% of C3−/− mice died (p=0.0008, n=20 in each group). While WT mice showed a moderate to severe GVHD in the skin, intestine, liver, lung and kidney, C3−/− mice had mild changes in these organs, reflected in a significantly lower GVHD scores compared to WT mice.
Donor T cells proliferation is a critical step in development of GVHD. Therefore, we analyzed donor-derived T cells in C3−/− mice 7 days post-transplant, and found a significantly lower number of CD4+ and CD8+ T cells in spleen, lymph node and Peyer's patches compared to those in WT mice. Complement deficiency not only affected the number of T cells but also their polarization. In the spleen and lymph nodes of C3−/−mice, we found a significantly lower number of IFNg-producing T cells and Th17+IFNg+ cells compared to WT recipients, consistent with a reduced Th1 and Th17+ differentiation of donor T cells in C3−/− recipient mice.
Since the interaction between recipient-derived dendritic cells (DCs) and donor T cells is one of the initial events in the pathogenesis of the alloimmune response in GVHD, we analyzed both lymphoid and nonlymphoid DCs in the C3−/− recipient mice. Murine lymphoid DCs are divided into CD8a+ and CD8a− subsets that stimulate Th1 and Th2 cells, respectively. We detected a significantly lower number of CD8a+ (Th1-driven) and higher number of CD8a− (Th2-driven) DCs in the spleen of C3−/− recipient compared to WT mice. Additionally, the number of CD8a+ DCs was significant decreased in lymph node of C3−/− mice. In the nonlymphoid tissues, CD103+ DCs are developmentally and functionally related to the CD8a+ DCs. We studied DCs in the lung, liver, intestine and skin of recipient mice and found a significant reduction in the number of CD103+ DCs in the lung of C3−/− compared to WT recipient mice. Thus, C3 deficiency is associated with a decrease in Th1-driven DCs in both lymphoid (CD8a+) and nonlymphoid organs (CD103+) resulting in a reduced donor Th1 differentiation in C3−/− recipient mice.
In the present study, we show for the first time that complement plays a role in GVHD. Our results are consistent with the findings of previous studies showing that C3 production by DCs in allograft is essential for maturation of DCs, effective antigen presentation to alloreactive T cells, and the development of Th1 response. We demonstrated that a similar effect of complement after BMT might be important in regulating Th1-driven DC activation and donor Th1/Th17differentiation, and in determining the severity of GVHD. Our study improves the understanding of the molecular mechanisms of GVHD and provides a rationale for using complement inhibitors as a novel potential therapeutic tool in GVHD.
Disclosures:
No relevant conflicts of interest to declare.
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