Target antigens determine graft-versus-host disease phenotype
Target antigens determine graft-versus-host disease phenotype
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DOI：
10.4049/jimmunol.173.9.5467
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发表时间：
2004-11-01
影响因子：
4.4
通讯作者：
Shlomchik, WD
中科院分区：
文献类型：
--
作者：
Kaplan, DH;Anderson, BE;Shlomchik, WD
慢性移植物抗宿主病(CGVHD)是异基因干细胞移植中日益常见的并发症。CGVHD的表型因患者不同而不同；尤其是，部分患者会出现广泛的皮肤纤维化。同样，移植物抗宿主病(GVHD)在近交系小鼠供受者配对中是不同的，表明疾病表型的遗传成分。B10.D2-->；BALB/c(H-2(D))菌株配对独特地概括了人皮肤纤维化cGVHD的关键病理特征。为了区分这种遗传成分是由于调节免疫反应的基因的差异还是由于目标特定的AGS，我们询问了皮肤显性cGVHD是否也发生在B10-->；BALB.B(H-2(B))和B10.BR-->；BALB.K(H-2(K))MHC-同源配对中。由于每种MHC单倍型呈现不同的多肽和选择不同的T细胞谱系，每对供受者的GVHD无疑针对不同的AGS。我们发现，与BALB/c受体相比，BALB.B小鼠从未表现出皮肤病，而BALB.K小鼠出现了一种改良形式的皮肤病。相反，BALB.B和BALB.K受体发生了BALB/c小鼠所没有的全身性移植物抗宿主病。此外，在(B10×B10.D2)F-1->；(BALB.B×BALB/c)F-1H-2(b/d)移植中，受体同时发生皮肤和全身疾病。因此，免疫显性AGS的选择决定了GVHD的靶点和特征，为深入了解不同类型GVHD的遗传学基础提供了依据。
Chronic graft-vs-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Phenotypically, cGVHD differs from patient to patient; in particular, a subset of patients develops extensive cutaneous fibrosis. Similarly, graft-vs-host disease (GVHD) is distinct in inbred murine donor:recipient pairings, indicating a genetic component to disease phenotype. The B10.D2 --> BALB/c (H-2(d)) strain pairing uniquely recapitulates key pathologic features of fibrotic human cutaneous cGVHD. To distinguish whether this genetic component is due to differences in genes that modulate immune responses or to the specific Ags targeted, we asked whether skin-dominant cGVHD also develops in the B10 --> BALB.B (H-2(b)) and B10.BR --> BALB.K (H-2(k)) MHC-congenic pairings. Because each MHC haplotype presents different peptides and selects different T cell repertoires, GVHD in each donor:recipient pair undoubtedly targets different Ags. We found that, in contrast to BALB/c recipients, BALB.B mice never manifested skin disease while BALB.K mice developed a modified form of skin disease. Instead, BALB.B and BALB.K recipients developed systemic GVHD which was absent in BALB/c mice. Moreover, in (B10 X B10.D2)F-1 --> (BALB.B X BALB/c)F-1 H-2(b/d) transplants, recipients developed both cutaneous and systemic disease. Thus, the selection of immunodominant Ags determines the target and character of GVHD, providing insight into the genetic basis for different forms of GVHD.