Thomas J, Alqaisi M, Cunningham P, Carver M, Rebellato L, Gross U, Patselas T, Araneda D, Thomas F
Department of Surgery, East Carolina University School of Medicine, Greenville, North Carolina 27858.
Transplantation. 1992 Feb;53(2):247-58. doi: 10.1097/00007890-199202010-00001.
The effectiveness of fractionated TLI in promoting allograft tolerance without chronic drug therapy is well established experimentally. TLI has not been widely applied in clinical transplantation, largely due to logistic and medical limitations of pretransplant TLI conditioning. Potential use of posttransplant TLI (PT-TLI) has not been critically evaluated. In this study we investigated PT-TLI in combination with rabbit antithymocyte globulin (RATG) in the absence of chronic immunosuppressive drugs as a strategy for inducing long-term kidney allograft acceptance. Recipients were studied with and without infusion of DR-CD3- donor bone marrow cells (DBMC). Normal rhesus monkeys, which received no pretransplant treatment, underwent bilateral intrinsic nephrectomy and splenectomy at the time of transplantation. RATG was administered daily for 3-5 consecutive days beginning on day 0. A total dose of 500-625 cGy of fractionated TLI was given in 4-5 treatments at 125 cGy per day beginning on day +1. Whereas neither PT-TLI nor RATG monotherapy induced long-term graft acceptance in splenectomized recipients, the combination of these modalities was remarkable in promoting long-term allograft acceptance without immunosuppressive drug therapy. Of 4 recipients given RATG x 5, splenectomy and PT-TLI, all were free of acute rejection. Of these, 3/4 had graft survivals greater than 100 days, 2/4 were greater than 150 days and 1/4 greater than 365 days. Of 5 recipients given this treatment plus an infusion of DR-CD3-DBMC, 4/5 grafts survived greater than 150 days and 3/5 still have normal functioning grafts at greater than 365 days. PT-TLI accentuated and prolonged changes in PBL subpopulations that were initially affected by RATG. Depressed levels of CD3+ cells were present for 4-5 months, with large numbers of circulating CD4+CD3- and especially CD8+ CD3- cells. In addition, antibody responses to RATG and alloantigens were suppressed in PT-TLI-treated recipients. Overall, the combination of PT-TLI, splenectomy, and RATG was found to be effective in promoting long-term allograft acceptance without chronic immunosuppressive drug therapy. The infusion of DR-CD3- DBMC in recipients treated with PT-TLI, RATG and splenectomy appeared to further increase the incidence of stable long-term survivors. If infectious complications can be improved, this approach may provide a clinically applicable posttransplant treatment strategy for inducing functional allograft tolerance.
分次全身照射（TLI）在不进行长期药物治疗的情况下促进同种异体移植耐受的有效性已在实验中得到充分证实。TLI尚未广泛应用于临床移植，主要是由于移植前TLI预处理存在后勤和医学方面的限制。移植后TLI（PT-TLI）的潜在用途尚未得到严格评估。在本研究中，我们研究了PT-TLI联合兔抗胸腺细胞球蛋白（RATG）在无慢性免疫抑制药物的情况下作为诱导长期肾移植接受的策略。对接受和未接受输注DR-CD3-供体骨髓细胞（DBMC）的受者进行了研究。未接受移植前治疗的正常恒河猴在移植时进行了双侧肾切除术和脾切除术。从第0天开始连续3-5天每天给予RATG。从第+1天开始，分4-5次给予总量为500-625 cGy的分次TLI，每次125 cGy。然而，单独的PT-TLI或RATG单药治疗均未在脾切除的受者中诱导长期移植接受，而这些方法的联合在不使用免疫抑制药物治疗的情况下促进长期移植接受方面效果显著。在4名接受RATG×5、脾切除术和PT-TLI的受者中，所有受者均未发生急性排斥反应。其中，3/4的移植存活时间超过100天，2/4超过150天，1/4超过365天。在5名接受这种治疗并输注DR-CD3-DBMC的受者中，4/5的移植存活时间超过150天，3/5在超过365天时仍具有正常功能的移植肾。PT-TLI加剧并延长了最初受RATG影响的外周血淋巴细胞（PBL）亚群的变化。CD3+细胞水平降低持续4-5个月，伴有大量循环CD4+CD3-细胞，尤其是CD8+CD3-细胞。此外，PT-TLI治疗的受者对RATG和同种异体抗原的抗体反应受到抑制。总体而言，发现PT-TLI、脾切除术和RATG的联合在不进行慢性免疫抑制药物治疗的情况下有效促进长期移植接受。在接受PT-TLI、RATG和脾切除术治疗的受者中输注DR-CD3-DBMC似乎进一步增加了稳定长期存活者的发生率。如果能改善感染并发症，这种方法可能为诱导功能性移植耐受提供一种临床适用的移植后治疗策略。
