Demirci Gülçin, Amanullah Farhana, Kewalaramani Reshma, Yagita Hideo, Strom Terry B, Sayegh Mohamed H, Li Xian Chang
Department of Medicine, Harvard Medical School, and Division of Immunology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
J Immunol. 2004 Feb 1;172(3):1691-8. doi: 10.4049/jimmunol.172.3.1691.
Blocking both CD28 and CD154 costimulatory pathways can induce transplant tolerance in some, but not all, transplant models. Under stringent conditions, however, this protocol often completely fails to block allograft rejection. The precise nature of such CD28/CD154 blockade-resistant rejection is largely unknown. In the present study we developed a new model in which both CD28 and CD154, two conventional T cell costimulatory molecules, are genetically knocked out (i.e., CD28/CD154 double-knockout (DKO) mice) and used this model to examine the role of novel costimulatory molecule-inducible costimulator (ICOS), OX40, 4-1BB, and CD27 in mediating CD28/CD154-independent rejection. We found that CD28/CD154 DKO mice vigorously rejected fully MHC-mismatched DBA/2 skin allografts (mean survival time, 12 days; n = 6) compared with the wild-type controls (mean survival time, 8 days; n = 7). OX40 costimulation is critically important in skin allograft rejection in this model, as blocking the OX40/OX40 ligand pathway, but not the ICOS/ICOS ligand, 4-1BB/4-1BBL, or CD27/CD70 pathway, markedly prolonged skin allograft survival in CD28/CD154 DKO mice. The critical role of OX40 costimulation in CD28/CD154-independent rejection is further confirmed in wild-type C57BL/6 mice, as blocking the OX40/OX40 ligand pathway in combination with CD28/CD154 blockade induced long term skin allograft survival (>100 days; n = 5). Our study revealed a key cellular mechanism of rejection and identified OX40 as a critical alternative costimulatory molecule in CD28/CD154-independent rejection.
阻断CD28和CD154共刺激通路在某些但并非所有移植模型中均可诱导移植耐受。然而，在严格条件下，该方案常常完全无法阻断同种异体移植排斥反应。这种对CD28/CD154阻断具有抗性的排斥反应的确切性质在很大程度上尚不清楚。在本研究中，我们构建了一种新模型，其中传统的两种T细胞共刺激分子CD28和CD154均通过基因敲除（即CD28/CD154双敲除（DKO）小鼠），并利用该模型研究新型共刺激分子诱导性共刺激分子（ICOS）、OX40、4-1BB和CD27在介导不依赖CD28/CD154的排斥反应中的作用。我们发现，与野生型对照（平均存活时间，8天；n = 7）相比，CD28/CD154 DKO小鼠有力地排斥了完全MHC不匹配的DBA/2皮肤同种异体移植物（平均存活时间，12天；n = 6）。在该模型中，OX40共刺激在皮肤同种异体移植排斥反应中至关重要，因为阻断OX40/OX40配体通路，而非ICOS/ICOS配体、4-1BB/4-1BBL或CD27/CD70通路，可显著延长CD28/CD154 DKO小鼠皮肤同种异体移植物的存活时间。在野生型C57BL/6小鼠中，OX40共刺激在不依赖CD28/CD154的排斥反应中的关键作用得到进一步证实，因为联合阻断OX40/OX40配体通路与CD28/CD154可诱导皮肤同种异体移植物长期存活（>100天；n = 5）。我们的研究揭示了排斥反应的关键细胞机制，并确定OX40是不依赖CD28/CD154的排斥反应中的关键替代性共刺激分子。
