Bolling S F, Lin H, Wei R Q, Turka L A
Section of Thoracic Surgery, University of Michigan Medical Center, Ann Arbor, USA.
J Heart Lung Transplant. 1996 Sep;15(9):928-35.
Tolerance to alloantigen in transplant recipients could remove life-long dependence on immunosuppression. Evidence suggests that T-cell responses to alloantigen are dependent not only on T-cell receptor activation but also on costimulation by means of the CD28 receptor. The natural ligands for CD28, expressed on antigen-presenting cells, are B7 family members. CTLA4Ig (a soluble CD28 receptor analog) preferentially binds B7-1 and B7-2 and inhibits CD28 activation. Theoretically, T-cell receptor activation in the presence of alloantigen during CTLA4Ig blockade of CD28-B7 costimulation could render T cells tolerant to that specific alloantigen. In vivo CTLA4Ig significantly increases allograft survival times and can lead to transplantation tolerance. In the rat cardiac allograft model, donor-specific transfusion must be combined with CTLA4Ig to induce tolerance. Previously our laboratory has shown that timing is crucial in the induction of tolerance.
We examined the effect of differing routes (intravenous, portal vein, or intrathymic), as well as timing (before, at, and after transplantation), of donor-specific transfusion on its ability to synergize with CTLA4Ig using a rat heterotopic major histocompatibility complex-mismatch heart transplant model.
We found that tolerance induced by CTLA4Ig and donor-specific transfusion was antigen specific and that timing, but not route of donor-specific antigen administration, had an impact on tolerance induction. Intravenous donor-specific transfusion had a beneficial effect on allograft survival equal to portal vein and intrathymic routes, which have been believed to be more tolerogenic.
Almost universal engraftment can be induced with a combination of intravenous donor-specific transfusion at transplantation plus inhibition of CD28 activation by CTLA4Ig 48 hours after transplantation-a regimen which could have clinical application.
移植受者对同种异体抗原产生耐受可消除对免疫抑制的终身依赖。有证据表明，T细胞对同种异体抗原的反应不仅取决于T细胞受体的激活，还取决于通过CD28受体的共刺激。抗原呈递细胞上表达的CD28天然配体是B7家族成员。CTLA4Ig（一种可溶性CD28受体类似物）优先结合B7-1和B7-2并抑制CD28激活。从理论上讲，在CTLA4Ig阻断CD28-B7共刺激过程中，同种异体抗原存在时T细胞受体的激活可使T细胞对该特定同种异体抗原产生耐受。体内CTLA4Ig可显著延长同种异体移植物存活时间，并可导致移植耐受。在大鼠心脏同种异体移植模型中，必须将供体特异性输血与CTLA4Ig联合使用才能诱导耐受。此前我们实验室已表明时机在诱导耐受中至关重要。
我们使用大鼠异位主要组织相容性复合体不匹配心脏移植模型，研究了供体特异性输血的不同途径（静脉内、门静脉或胸腺内）以及时机（移植前、移植时和移植后）对其与CTLA4Ig协同作用能力的影响。
我们发现CTLA4Ig和供体特异性输血诱导的耐受具有抗原特异性，并且时机而非供体特异性抗原给药途径对耐受诱导有影响。静脉内供体特异性输血对同种异体移植物存活的有益作用与门静脉和胸腺内途径相当，而后两者一直被认为更具耐受性。
移植时静脉内给予供体特异性输血并在移植后48小时用CTLA4Ig抑制CD-28激活的联合方案可诱导几乎普遍的植入，该方案可能具有临床应用价值。
