Minor Histocompatibility Antigen UTY as Target for Graft-versus-Leukemia and Graft-versus-Haematopoiesis in the Canine Model
Minor Histocompatibility Antigen UTY as Target for Graft-versus-Leukemia and Graft-versus-Haematopoiesis in the Canine Model
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DOI：
10.1111/sji.12011
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发表时间：
2013-01-01
影响因子：
3.7
通讯作者：
Schmetzer, H. M.
中科院分区：
文献类型：
--
作者：
Bund, D.;Buhmann, R.;Schmetzer, H. M.
由于Y编码的次要组织相容性抗原在移植物抗白血病(GVL)效应的背景下被女性同种异体免疫效应淋巴细胞识别，与女性干细胞捐献者的男性患者相比，男性患者的预后更好。我们在犬模型中提供的数据表明，次要组织相容性抗原UTY可能是进一步改善异基因干细胞移植后GVL免疫反应的有希望的靶点。用负载3倍扩增的HLAA2限制性UTY衍生肽的自体DC体外刺激雌性犬UTY特异性T细胞(CTL)，检测3/6只雌性犬的特异性T细胞应答。CTL特异性识别/裂解自体女性多肽负载的DC，但不识别幼稚的自体女性DC和单核细胞。它们主要识别骨髓，并以MHC-I限制性的方式识别DLA同系雄性仔鼠的DC、单核细胞、PBMCs和B细胞以及多肽负载的T2细胞。用DLA完全相同的雄性PBMCs刺激雌性犬，在体内也获得了UTY/雄性特异性反应。总而言之，我们在狗身上演示了自然的UTY处理和呈现。我们发现，HLAA2限制性UTY多肽可以特异性地刺激雌性犬的CTL，从而能够识别DLA相同的雄性细胞，主要是BM细胞。这些观察结果表明，UTY是一种有希望的候选抗原，可在免疫治疗过程中改善GVL反应。
Male patients with female-stem-cell donors have better prognosis compared to female-to-male combinations due to Y-encoded minor histocompatibility antigens recognized by female-alloimmune-effector lymphocytes in the context of a graft-versus-leukemia (GvL) effect. We provide data in a dog-model that the minor histocompatibility antigen UTY might be a promising target to further improve GvL-immune reactions after allogeneic-stem-cell transplantations. Female-canine-UTY-specific T cells (CTLs) were stimulated in vitro using autologous-DCs loaded with three HLA-A2-restricted-UTY-derived peptides (3-fold-expansion), and specific T cell responses were determined in 3/6 female dogs. CTLs specifically recognized/lysed autologous-female-peptide-loaded DCs, but not naive-autologous-female DCs and monocytes. They mainly recognized bone-marrow (BM) and to a lower extent DCs, monocytes, PBMCs and B-cells from DLA-identical-male littermates and peptide-loaded T2-cells in an MHC-I-restricted manner. A UTY-/male-specific reactivity was also obtained in vivo after stimulation of a female dog with DLA-identical-male PBMCs. In summary, we demonstrated natural UTY processing and presentation in dogs. We showed that female-dog CTLs were specifically stimulated by HLA-A2-restricted-UTY peptides, thereby enabling recognition of DLA-identical-male cells, mainly BM cells. These observations suggest UTY as a promising candidate-antigen to improve GvL-reactions in the course of immunotherapy.