PREVENTION OF GRAFT-VERSUS-HOST DISEASE BY TARGETING ANTIGEN-PRESENTING CELLS AND BY TOLERANCE INDUCTION

我们首先研究确定GVHD小鼠模型中最关键的抗原呈递细胞（APCs）。我们发现宿主，而不是供体，衍生的树突状细胞（dc）单独足以引起GVHD。相比之下，宿主来源的B细胞在体内不能诱导GVHD。这些结果表明，选择性消除或抑制宿主apc可能是抑制GVHD诱导的一种有希望的策略。我们还测试了几种诱导耐受性的免疫学方法是否可以在GVHD小鼠模型中再次用于抑制GVHD。我们研究了刺激宿主NKT细胞是否可以调节小鼠的急性移植物抗宿主病（GVHD）。同种异体骨髓移植后第0天给受体小鼠注射人工合成的NKT细胞配体α-半乳糖神经酰胺（α-GalCer），可促进供体T细胞Th2极化，并显著降低血清TNF-a （GVHD的关键介质）。受体小鼠单次注射α-GalCer可显著降低GVHD的发病率和死亡率。然而，在NKT细胞缺陷CD1d敲除（CD1d^<-/->）或IL-4^<-/->受体小鼠或STAT6^<-/->小鼠作为供体小鼠时，同样的处理不能赋予对GVHD的保护作用，这表明宿主NKT细胞、宿主IL-4的产生和供体T细胞介导的Th2细胞因子反应在α-GalCer对GVHD的保护作用中起关键作用。因此，通过NKT配体刺激宿主NKT细胞可以通过stat6依赖机制诱导供体T细胞的Th2极化来调节急性GVHD，这可能是预防GVHD的一种新策略。

We first studied to determine the most critical antigen-presenting cells(APCs) in mouse models of GVHD. We found that hostr, but not donor, derived dendritic cells(DCs) alone are sufficient to cause GVHD. In contrast, host-derived B cells atone were not able to induce GVHD in vivo. These results suggest that selective elimination or suppression of host APCs can be a promising strategy to inhibit the induction of GVHD. We also tested whether several irnmunological approaches to induce tolerance can be applied to suppress GVHD again in mouse models of GVHD. We have investigated whether stimulation of host NKT cells could modulate acute graft-versus-host disease(GVHD) in mice. Injection of the synthetic NKT cell ligandα-galactosylceramide(α-GalCer) to recipient mice on day 0 following allogeneic bone marrow transplantation promoted Th2 polarization of donor T cells and a dramatic reduction of serum TNF-a, a critical mediator of GVHD. A single injection of α-GalCer to recipient mice significantly reduced morbidity and mortality of GVHD. However, the same treatment was unable to confer protection against GVHD in NKT cell deficient CD1d knockout (CD1d^<-/->) or IL-4^<-/-> recipient mice or when STAT6^<-/-> mice were used as donors, indicating the critical role of host NKT cells, host production of IL-4,and Th2 cytokine responses mediated by donor T cells on the protective effects of α-GalCer against GVHD. Thus stimulation of host NKT cells through administration of NKT ligand can regulate acute GVHD by inducing Th2 polarization of donor T cells via STAT6-dependent mechanisms and might represent a novel strategy for prevention of GVHD.