Blood, Vol. 94 No. 8 (October 15), 1999:
pp. 2915-2922
Viral Hyperinfection of the Central Nervous System and High
Mortality After Hematopoietic Stem Cell Transplantation for
Treatment of Theiler's Murine Encephalomyelitis Virus-Induced
Demyelinating Disease
Richard K. Burt,
Josette Padilla,
Mauro C. Dal Canto, and
Stephen
D. Miller
From the Department of Medicine, the Department of
Microbiology-Immunology and Interdepartmental Immunobiology Center, the
Department of Pathology, and Robert H. Lurie Cancer Center,
Northwestern University Medical School, Chicago, IL.
Theiler's murine encephalomyelitis virus (TMEV) establishes a
persistent infection in the central nervous system (CNS) leading to an
inflammatory demyelinating disease of the CNS in which the histology
and clinical course is similar to multiple sclerosis (MS). Disease
pathogenesis is primarily due to T-cell-mediated destruction of
myelin, which has been attributed to cytopathic effects of the virus,
but immune-mediated destruction of myelin mediated via both
virus-specific and myelin-specific T cells appear to play the major
role. To determine if bone marrow transplantation would be an effective
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
irradiation, 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
(C57Bl/6 × DBA/2)F1 (B6D2) donors. 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 proteins
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-cell responses are important in prevention of lethal
cytopathic CNS effects from TMEV. Relevant to the clinical use of bone
marrow transplantation, attempts to ablate the immune system in
viral-mediated immune diseases or virus-initiated autoimmune disease
may have acute and lethal consequences. Our results raise concern about the attempted use of autologous hematopoietic transplantation in
patients with MS, an autoimmune disease with a suspected virus etiology, particularly if the graft is aggressively
depleted of lymphocytes.
