Karussis D M, Slavin S, Lehmann D, Mizrachi-Koll R, Abramsky O, Ben-Nun A
Department of Neurology, Hadassah Hebrew University Hospital, Jerusalem, Israel.
J Immunol. 1992 Mar 15;148(6):1693-8.
Experimental autoimmune encephalomyelitis (EAE) is an inducible autoimmune disease widely used as a model of the acute/relapsing stage of multiple sclerosis. In the present study we examined the effect of acute immunosuppression induced by total body irradiation (TBI) (900 to 1100 centigray (cGy)) or by a single high dose of cyclophosphamide (CY) (300 mg/kg), followed by syngeneic bone marrow transplantation (SBMT), on the development of EAE in SJL/J mice. EAE was induced in SJL/J mice by immunization with spinal cord homogenate in adjuvant. Treatment with TBI (900 cGy) and SBMT on day 6 postimmunization caused a delayed onset and a marked reduction in the incidence and severity of EAE. A higher dose of irradiation (1100 cGy) or the administration of CY followed by SBMT completely abrogated the development of paralysis. None of the 21 mice treated with CY and SBMT, and only 1 of 7 mice treated with TBI (1100 cGy) and SBMT developed clinical signs of EAE during a period of 3 months. Furthermore, mice treated with CY and SBMT became resistant to rechallenge with the same encephalitogenic inoculum. In addition, the lymphocytes obtained from these mice did not proliferate in vitro in response to myelin basic protein or tuberculin-purified protein derivative, unlike lymphocytes from immunized but untreated animals. This absence of reactivity was not associated with alterations in the proportion of the L3T4 and Lyt-2 T-cell subsets nor with a loss in T cell competence as evidenced by the full response of lymphocytes to the T cell mitogen Con A and to a nonrelevant Ag (OVA). Our results indicate that the elimination of effector lymphocytes either by myeloablative doses of CY or ionizing irradiation followed by rescue with SBMT inhibits the development of the autoimmune process in EAE and leads to induction of tolerance to the immunizing Ag by newly developing lymphocytes. This approach of combining immunoablation and reconstitution with autologous bone marrow transplantation may be applicable in the treatment of life-threatening neurologic autoimmune diseases.
实验性自身免疫性脑脊髓炎（EAE）是一种可诱导的自身免疫性疾病，被广泛用作多发性硬化症急性/复发期的模型。在本研究中，我们检测了全身照射（TBI）（900至1100厘戈瑞（cGy））或单次高剂量环磷酰胺（CY）（300mg/kg）诱导的急性免疫抑制，随后进行同基因骨髓移植（SBMT），对SJL/J小鼠EAE发病的影响。通过在佐剂中用脊髓匀浆免疫诱导SJL/J小鼠发生EAE。免疫后第6天用TBI（900cGy）和SBMT治疗导致EAE发病延迟，发病率和严重程度显著降低。更高剂量的照射（1100cGy）或CY给药后进行SBMT完全消除了麻痹的发生。21只接受CY和SBMT治疗的小鼠中没有一只，而7只接受TBI（1100cGy）和SBMT治疗的小鼠中只有1只在3个月内出现EAE的临床症状。此外，接受CY和SBMT治疗的小鼠对相同的致脑炎接种物再次攻击具有抗性。此外，与免疫但未治疗动物的淋巴细胞不同，从这些小鼠获得的淋巴细胞在体外对髓鞘碱性蛋白或结核菌素纯化蛋白衍生物没有增殖反应。这种反应性的缺失与L3T4和Lyt-2 T细胞亚群比例的改变无关，也与T细胞能力的丧失无关，淋巴细胞对T细胞有丝分裂原Con A和无关抗原（OVA）的完全反应证明了这一点。我们的结果表明，通过大剂量CY或电离辐射清除效应淋巴细胞，随后用SBMT进行挽救，可抑制EAE中自身免疫过程的发展，并导致新发育的淋巴细胞对免疫抗原产生耐受性。这种将免疫消融与自体骨髓移植重建相结合的方法可能适用于治疗危及生命的神经自身免疫性疾病。
