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

同种异体干细胞移植通常是治疗恶性血液病的唯一方法。用健康的供体移植物替代患者的造血系统，允许供体来源的t淋巴细胞对患者残留的恶性细胞产生免疫反应，从而导致长期的缓解。然而，这种免疫反应不是选择性地针对恶性患者细胞，但也可能攻击和损害患者健康的非造血细胞，导致有害的移植物抗宿主病。这种副作用通常难以治疗，并且仍然是同种异体干细胞移植后发病和死亡的主要原因。到目前为止，将移植物抗白血病效应和移植物抗宿主病相分离是不可能的。分离这两种作用的一种可能性是利用CD4+ t细胞，因为HLA II类分子仅在造血系统中表达。然而，在炎症和细胞因子释放过程中，非造血细胞也可以上调HLA II类分子。最近，我们发现HLA II类限制性抗原有两个亚群。一组抗原存在于所有HLA II类表达细胞中，并且独立于非经典HLA II类分子HLA- dm的表达。这些抗原被称为抗dm。另一组抗原的呈递被HLA-DM废除，仅通过HLA-DO的共表达重建。这些抗原被称为dm敏感抗原。与经典HLA II类分子相似，HLA- dm的表达是由干扰素- γ等细胞因子诱导的。相反，HLA-DO不受炎症细胞因子的上调。因此，针对dm敏感抗原的CD4+ t细胞可能会诱导选择性移植物抗白血病效应，而不会引起移植物抗宿主病。该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原发性和继发性免疫反应。此外，我们将研究它们在介导移植物抗肿瘤效应以及移植物抗宿主病发生率方面的潜力，并与dm抗性抗原进行比较。从长远来看，该项目将为治疗接受同种异体干细胞移植的恶性血液病患者奠定基础，这些患者使用额外的CD4+供体淋巴细胞靶向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.