Inherited demyelinating neuropathies are chronically disabling human disorders caused by various genetic defects, including deletions, single site mutations, and duplications in the respective myelin genes. We have shown in a mouse model of one distinct hereditary demyelinating neuropathy (heterozygous P0-deficiency, P0+-) that an additional null mutation in the recombination activating gene-1 (RAG-1--) leads to a substantially milder disorder, indicating a disease modifying role of T-lymphocytes. In the present study, we addressed the role of lymphocytes in the mouse model by reconstituting bone marrow of P0+-/RAG-1-- mice with bone marrow from immunocompetent wild-type mice. We compared the pathology and nerve conduction in double mutant mice (P0+-/RAG-1-- on a C57BL/6 background) with that in double mutants after receiving a bone marrow transplant. We found that the milder demyelination seen in the lymphocyte-deficient P0+-/RAG-1-- mutants was reverted to the more severe pathology by reestablishing a competent immune system by bone marrow transfer. These data corroborate the concept that the immune system contributes substantially to the pathologic process in this mouse model and may open new avenues to ameliorate human hereditary neuropathies by exploiting immunosuppressive treatments.
Copyright 2001 Academic Press.