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

细胞内抗原加工在诱导选择性移植物抗白血病效应（无移植物抗宿主病）中的作用

• 批准号: 290078923
• 负责人: Privatdozentin Dr. Anita Kremer
• 金额: --
• 依托单位: Medizinische Klinik 5 -Hämatologie und Internistische Onkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290078923?language=en
• 关键词: role; intracellular; antigen; processing; induction

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.

同种异体干细胞移植通常是血液恶性肿瘤患者的唯一治疗方法。用健康的供体移植物替代患者的造血系统，可以使供体来源的 T 淋巴细胞对患者残留的恶性细胞产生免疫反应，从而实现长期缓解。然而，这种免疫反应并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，并且仍然是同种异体干细胞移植后发病和死亡的主要原因。迄今为止不可能将移植物抗白血病效应和移植物抗宿主病协调分离。分离这两种效应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上表达。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，我们可以证明HLA II 类限制性抗原有两个亚组。一组抗原呈递于所有 HLA II 类表达细胞上，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 DM 抗性。另一组抗原的呈递被 HLA-DM 消除，并且仅通过 HLA-DO 的共表达来重建。这些抗原被称为 DM 敏感的。类似于经典的HLA II类分子，HLA-DM的表达是由细胞因子如干扰素-γ诱导的。相比之下，HLA-DO 不会被炎症细胞因子上调。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，而不会产生移植物抗宿主病。该项目的首要目标是分析 DM 敏感抗原是否能够在体内诱导有效的初级和次级免疫反应。此外，我们将研究与 DM 抗性抗原相比，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。从长远来看，该项目应该为治疗血液恶性肿瘤患者奠定基础，这些患者接受同种异体干细胞移植，并使用针对DM敏感抗原的额外CD4+供体淋巴细胞，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。