PREVENTION AND REVERSAL OF ADOPTIVELY TRANSFERRED, CHRONIC RELAPSING EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS WITH A SINGLE HIGH-DOSE CYTOREDUCTIVE TREATMENT FOLLOWED BY SYNGENEIC BONE-MARROW TRANSPLANTATION

A chronic relapsing form of experimental autoimmune encephalomyelitis (CR-EAE) was induced in SJL/J mice by adoptive transfer of lymph node cells (LNC) sensitized to guinea pig myelin basic protein (GMBP). We e xamined the efficacy of high dose immunosuppressive regimens (cyclopho sphamide [CY] 300 mg/kg or total body irradiation [TBI] 900 cGy) follo wed by syngeneic bone marrow transplantation (SBMT) in prevention and treatment of already established CR-EAE. Treatment with TBI and SBMT o n day 5 after the induction of CR-EAE, just before the onset of clinic al signs, completely inhibited the appearance of the paralytic signs. The same treatment, applied 4 d after the clinical onset of the diseas e, led to a significant regression of the paralytic signs and to a tot al inhibition of spontaneous relapses during a follow-up period of 2 m o. Challenge of mice with GMBP+CFA 78 d after the passive induction of CR-EAE induced a relapse of the disease 7 d later in almost all of th e untreated mice; in contrast, the same challenge given to TBI+SBMT-tr eated mice caused a delayed relapse (30 d later) in only a minority (3 /7) of the challenged mice. In vitro lymphocytic proliferative respons es to GMBP and purified protein derivative were significantly, lower i n TBI+SBMT-treated mice before and after the GMBP challenge, although these mice were fully immunocompetent, as evidenced by their normal ly mphocytic proliferation to concanavalin A (ConA) and the FACS(R) analy sis of their lymphocytic subpopulations. A similar beneficial therapeu tic effect was observed in mice treated with CY followed by SBMT, afte r the onset of CR-EAE. Our results could support possible clinical app lications of similar therapeutic strategies, involving acute immunosup pression followed by stem cell transplantation and retolerization of t he reconstituting immune cells in life-threatening neurological and mu ltisystemic autoimmune diseases.