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 examined the efficacy of high dose immunosuppressive regimens (cyclophosphamide [CY] 300 mg/kg or total body irradiation [TBI] 900 cGy) followed by syngeneic bone marrow transplantation (SBMT) in prevention and treatment of already established CR-EAE. Treatment with TBI and SBMT on day 5 after the induction of CR-EAE, just before the onset of clinical signs, completely inhibited the appearance of the paralytic signs. The same treatment, applied 4 d after the clinical onset of the disease, led to a significant regression of the paralytic signs and to a total inhibition of spontaneous relapses during a follow-up period of 2 mo. 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 the untreated mice; in contrast, the same challenge given to TBI+SBMT-treated mice caused a delayed relapse (30 d later) in only a minority (3/7) of the challenged mice. In vitro lymphocytic proliferative responses to GMBP and purified protein derivative were significantly lower in TBI/SBMT-treated mice before and after the GMBP challenge, although these mice were fully immunocompetent, as evidenced by their normal lymphocytic proliferation to concanavalin A (ConA) and the FACS analysis of their lymphocytic subpopulations. A similar beneficial therapeutic effect was observed in mice treated with CY followed by SBMT, after the onset of CR-EAE. Our results could support possible clinical applications of similar therapeutic strategies, involving acute immunosuppression followed by stem cell transplantation and retolerization of the reconstituting immune cells in life-threatening neurological and multisystemic autoimmune diseases.
Karussis
D M
DM
Department of Neurology, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
Vourka-Karussis
U
U
Lehmann
D
D
Ovadia
H
H
Mizrachi-Koll
R
R
Ben-Nun
A
A
Abramsky
O
O
Slavin
S
S
D000818:Animals; D016026:Bone Marrow Transplantation; D001921:Brain / Q000473:pathology; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy*; D005260:Female; D006168:Guinea Pigs; D016219:Immunotherapy, Adoptive; D008198:Lymph Nodes / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D004676:Myelin Basic Protein / Q000008:administration & dosage; D013997:Time Factors; D014916:Whole-Body Irradiation
D004676:Myelin Basic Protein; D003520:Cyclophosphamide