Grazia Todd J, Plenter Robert J, Doan An N, Kelly Brian P, Weber Sarah M, Kurche Jonathan S, Cushing Susan O, Gill Ronald G, Pietra Biagio A
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Colorado Health Sciences Center, and the Children's Hospital, Denver, CO 80262, USA.
Transplantation. 2007 Jun 15;83(11):1449-58. doi: 10.1097/01.tp.0000265482.88936.b1.
Acute cardiac allograft rejection requires host, but not donor, expression of B7-1/B7-2 costimulatory molecules. However, acute cardiac rejection requires direct antigen presentation by donor-derived antigen presenting cells to CD4 T-cells and does not require indirect antigen presentation to CD4 T-cells. Given this discrepancy in the literature and that the consequence of allograft exposure in B7-deficient mice is unknown; the goal of the study was to examine the antidonor status of allografted B7-1/B7-2-deficient hosts.
C57Bl/6 B7-1/B7-2-/- mice were grafted with heterotopic BALB/c hearts. Recipients bearing long-term surviving allografts were used to examine the status of antidonor reactivity in vitro and in vivo. Tolerance was examined in vivo through adoptive transfer of splenocytes from graft-bearing animals to secondary immune-deficient Rag-1-/- hosts bearing donor-type or third-party cardiac allografts and by regulatory T-cell depletion with anti-CD25 antibody.
When transferred to B7-replete Rag-1-/- recipients, cells from naïve B7-1/B7-2-/- mice readily initiated cardiac allograft rejection. However, splenocytes transferred from long-term allograft acceptor B7-1/B7-2-/- hosts failed to reject donor-type hearts but acutely rejected third-party allografts. In addition, such cells did not reject (donorxthird-party) F1 allografts. Finally, in vivo depletion of regulatory T-cells did not prevent long-term acceptance.
Results demonstrate that B7-deficient T-cells are capable of acute cardiac allograft rejection in a B7-replete environment. Importantly, results also show that B7-deficient hosts do not simply ignore cardiac allografts, but rather spontaneously develop transferable, donor-specific tolerance and linked suppression in vivo. Interestingly, this tolerant state does not require endogenous CD4+CD25+ regulatory T-cells.
急性心脏移植排斥反应需要宿主而非供体表达B7-1/B7-2共刺激分子。然而，急性心脏排斥反应需要供体来源的抗原呈递细胞将抗原直接呈递给CD4 T细胞，而不需要将抗原间接呈递给CD4 T细胞。鉴于文献中存在这种差异，且B7缺陷小鼠同种异体移植暴露的后果尚不清楚；本研究的目的是检查同种异体移植的B7-1/B7-2缺陷宿主的抗供体状态。
将C57Bl/6 B7-1/B7-2基因敲除小鼠进行异位BALB/c心脏移植。使用长期存活同种异体移植的受体来检查体外和体内抗供体反应性的状态。通过将来自移植动物的脾细胞过继转移到携带供体类型或第三方心脏同种异体移植的二级免疫缺陷Rag-1基因敲除宿主中，并使用抗CD25抗体清除调节性T细胞，在体内检查耐受性。
当将来自未接触过抗原的B7-1/B7-2基因敲除小鼠的细胞转移到B7充足的Rag-1基因敲除受体时，这些细胞很容易引发心脏同种异体移植排斥反应。然而，从长期同种异体移植受体B7-1/B7-2基因敲除宿主转移的脾细胞未能排斥供体类型的心脏，但能急性排斥第三方同种异体移植。此外，此类细胞不会排斥（供体×第三方）F1同种异体移植。最后，体内清除调节性T细胞并不能阻止长期接受。
结果表明，B7缺陷的T细胞在B7充足的环境中能够引发急性心脏同种异体移植排斥反应。重要的是，结果还表明，B7缺陷的宿主并非简单地忽略心脏同种异体移植，而是在体内自发地形成可转移的、供体特异性的耐受性和连锁抑制。有趣的是，这种耐受状态不需要内源性CD4+CD25+调节性T细胞。
