Viral hyperinfection of the central nervous system and high mortality after hematopoietic stem cell transplantation for treatment of Theiler's murineencephalomyelitis virus-induced demyelinating disease
Rk. Burt et al., Viral hyperinfection of the central nervous system and high mortality after hematopoietic stem cell transplantation for treatment of Theiler's murineencephalomyelitis virus-induced demyelinating disease, BLOOD, 94(8), 1999, pp. 2915-2922
Theiler's murine encephalomyelitis virus (TMEV) establishes a persistent in
fection in the central nervous system (CNS) leading to an inflammatory demy
elinating disease of the CNS in which the histology and clinical course is
similar to multiple sclerosis (MS). Disease pathogenesis is primarily due t
o T-cell-mediated destruction of myelin, which has been attributed to cytop
athic effects of the virus, but immune-mediated destruction of myelin media
ted via both virus-specific and myelin-specific T cells appear to play the
major role, To determine if bone marrow transplantation would be an effecti
ve therapy for a virus-initiated autoimmune disease and to better separate
viral cytopathic effects from immune-mediated demyelination, we ablated the
immune system of TMEV-infected animals with 1,100 cGy total body irradiati
on, and then the animal's immunity was reconstituted by transplantation of
disease-susceptible SJL/J mice with syngeneic marrow or disease-susceptible
DBA/2J with marrow from disease-resistant (C57BI/6 x DBA/2)F1 (B6D2) donor
s. Hematopoietic transplant performed after onset of disease resulted in 42
% mortality in SJL/J syngeneic transplants, 47% mortality in diseased DBA2
recipients restored with marrow from naive B6D2 donors, and 12% in diseased
DBA2 recipients receiving marrow from B6D2 donors previously infected with
TMEV. Delayed type hypersensitivity (DTH) to both virion and myelin protei
ns was decreased in surviving mice that underwent transplantation; however,
CNS viral titers were significantly elevated compared with nontransplanted
controls, We conclude that a functional immune system with appropriate T-c
ell responses are important in prevention of lethal cytopathic CNS effects
from TMEV. Relevant to the clinical use of bone marrow transplantation, att
empts to ablate the immune system in viral-mediated immune diseases or viru
s-initiated autoimmune disease may have acute and lethal consequences. Our
results raise concern about the attempted use of autologous hematopoietic t
ransplantation in patients with MS, an autoimmune disease with a suspected
virus etiology, particularly if the graft is aggressively depleted of lymph
ocytes. (C) 1999 by The American Society of Hematology.