The role of intracellular antigen processing for the induction of a selective graft-versus-leukemia effect without graft versus host disease

异基因干细胞移植通常是恶性血液病患者唯一的治愈性治疗。患者的造血系统被健康的供体移植物替代，允许供体来源的T淋巴细胞对患者的残留恶性细胞产生免疫应答，从而导致长期缓解。然而，这种免疫应答不是选择性地针对恶性患者细胞，而是还可能攻击和损害患者的健康非造血细胞，导致有害的移植物抗宿主病。这种副作用通常难以治疗，并且仍然是异基因干细胞移植后发病率和死亡率的主要原因。目前尚不可能将移植物抗白血病效应和移植物抗宿主病分开。分离这两种效应的一种可能性是利用CD 4 + T细胞，因为HLA II类分子仅在造血系统上表达。然而，在炎症和细胞因子释放期间，非造血细胞也可以上调HLA II类分子。最近，我们可以表明存在两个HLA II类限制性抗原亚组。一组抗原呈递在所有表达HLA II类的细胞上，并且不依赖于非经典HLA II类分子HLA-DM的表达。这些抗原被称为DM抗性。另一组抗原的呈递被HLA-DM消除，并且仅通过HLA-DO的共表达重建。这些抗原被称为DM敏感性抗原。类似于经典的HLA II类分子，HLA-DM的表达由细胞因子如干扰素-γ诱导。相反，HLA-DO不被炎性细胞因子上调。因此，针对DM敏感性抗原的CD 4 + T细胞可能允许诱导选择性移植物抗白血病效应，而不会发生移植物抗宿主病。本项目的第一个目的是分析DM敏感抗原是否能够在体内诱导有效的初次和二次免疫应答。此外，我们将研究它们在介导移植物抗肿瘤效应以及与DM耐药抗原相比的移植物抗宿主病发病率方面的潜力。从长远来看，该项目应奠定基础，治疗血液恶性肿瘤患者进行异基因干细胞移植与额外的CD 4+供体淋巴细胞直接针对DM敏感抗原，以诱导更有效的抗肿瘤免疫反应，降低移植物抗宿主病的风险。

Allogeneic stem cell transplantation is often the only curative treatment for patients with hematological malignancies. The replacement of the patient`s hematopoietic system by a healthy donor graft allows an immunological response of donor derived T-lymphocytes against residual malignant cells of the patient thereby leading to long-lasting remissions. This immune response, however, is not selectively directed against malignant patient cells, but may also attack and damage healthy non-hematopoietic cells of the patient leading to detrimental graft-versus-host disease. This side effect is often difficult to treat and is still the major cause for morbidity and mortality after allogeneic stem cell transplantation. A concerted separation of graft-versus-leukemia effect and graft-versus-host disease is so far not possible. One possibility to separate these two effects is to exploit CD4+ T-cells, since HLA class II molecules are only expressed on the hematopoietic system. However, during inflammation and cytokine release non-hematopoietic cells can also up-regulate HLA class II molecules. Recently, we could show that there are two subgroups of HLA class II restricted antigens. One group of antigens is presented on all HLA class II expressing cells and is independent of the expression of the non-classical HLA class II molecule HLA-DM. These antigens are called DM-resistant. The presentation of the other group of antigens is abolished by HLA-DM and only reconstituted by co-expression of HLA-DO. Those antigens are called DM-sensitive. Similar to the classical HLA class II molecules expression of HLA-DM is induced by cytokines such as interferon -gamma. HLA-DO in contrast is not up-reguated by inflammatory cytokines. Therefore, CD4+ T-cells directed against DM-sensitive antigens may allow induction of a selective graft-versus-leukemia effect without graft-versus-host disease. The first aim of this project is to analyze whether DM-sensitive antigens are capable of inducing a potent primary and secondary immune response in vivo. Further, we will investigate their potential in mediating graft-versus-tumor effect as well as the incidence of graft-versus-host disease as compared to DM-resistant antigens. On the long run this project should lay the basis for treating patients with hematological malignancies that undergo allogeneic stem cell transplantation with additional CD4+ donor lymphocytes directed against DM-sensitive antigens in order to induce a more potent anti-tumor immune response with reduced risk for graft-versus-host disease.