Prevention of experimental autoimmune encephalomyelitis and induction of tolerance with acute immunosuppression followed by syngeneic bone marrow transplantation.
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.
Karussis
D M
DM
Department of Neurology, Hadassah Hebrew University Hospital, Jerusalem, Israel.
Slavin
S
S
Lehmann
D
D
Mizrachi-Koll
R
R
Abramsky
O
O
Ben-Nun
A
A
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D003520:Cyclophosphamide / Q000494:pharmacology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control*; D005260:Female; D005434:Flow Cytometry; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014916:Whole-Body Irradiation
D003520:Cyclophosphamide