Womer Karl L, Stone James R, Murphy Barbara, Chandraker Anil, Sayegh Mohamed H
Laboratory of Immunogenetics and Transplantation, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Masachussets.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Masachussets.
J Am Soc Nephrol. 2001 Nov;12(11):2500-2506. doi: 10.1681/ASN.V12112500.
Recent clinical and experimental evidence suggests that indirect allorecognition may promote the development of chronic rejection, but definitive experimental studies are lacking. To study the contribution of indirect allorecognition to chronic rejection, naïve Lewis (RT1(1)) rats were immunized with synthetic Wistar Furth (WF) class II-RT1(u).D (HLA-DR-like) or -RT1(u).B (HLA-DQ-like) or class I-RT1(u).A (HLA-A-like) peptides emulsified in complete Freund's adjuvant 7 d before transplantation (n = 5 to 7/group). Experimental and control animals then acted as recipients of fully mismatched WF vascularized cardiac allografts. Recipients received immunosuppression in the form of cyclosporine at a tapering dose that allows for long-term allograft survival. Animals were sacrificed at either 3 or 6 mo, with allograft arterial luminal occlusion scored on elastin stains by a blinded observer. At 3 mo, mean vessel scores were significantly higher in the RT1(u).A-immunized versus class II-immunized and control groups (P < 0.05). By 6 mo, there was progression of chronic allograft vasculopathy and a significantly higher mean vessel score in the RT1(u).A- and RT1(u).D-immunized versus RT1(u).B and control groups (P < 0.05). In vitro studies show evidence of shifting MHC allopeptide immunogenicity. It was concluded that T cells primed by specific donor class I and II MHC allopeptides promote the development of chronic vascularized allograft rejection. These novel observations provide definitive evidence of a link between indirect allorecognition and the development and progression of chronic rejection.
近期的临床和实验证据表明，间接同种异体识别可能会促进慢性排斥反应的发展，但缺乏确凿的实验研究。为了研究间接同种异体识别对慢性排斥反应的作用，在移植前7天，将新生的Lewis（RT1(1)）大鼠用完全弗氏佐剂乳化的合成Wistar Furth（WF）II类-RT1(u).D（HLA-DR样）或-RT1(u).B（HLA-DQ样）或I类-RT1(u).A（HLA-A样）肽进行免疫（每组n = 5至7只）。然后，实验动物和对照动物作为完全不匹配的WF血管化心脏同种异体移植物的受体。受体接受逐渐减量的环孢素形式的免疫抑制，以实现同种异体移植物的长期存活。在3个月或6个月时处死动物，由一位不知情的观察者对弹性蛋白染色的同种异体移植动脉管腔闭塞情况进行评分。在3个月时，RT1(u).A免疫组的平均血管评分显著高于II类免疫组和对照组（P < 0.05）。到6个月时，慢性同种异体移植物血管病变有所进展，RT1(u).A免疫组和RT1(u).D免疫组的平均血管评分显著高于RT1(u).B免疫组和对照组（P < 0.05）。体外研究显示了MHC同种异体肽免疫原性改变的证据。得出的结论是，由特定供体I类和II类MHC同种异体肽引发的T细胞促进了慢性血管化同种异体移植排斥反应的发展。这些新的观察结果提供了间接同种异体识别与慢性排斥反应的发生和进展之间存在联系的确凿证据。
