Bone marrow transfer from wild-type mice reverts the beneficial effect of genetically mediated immune deficiency in myelin mutants

Inherited demyelinating neuropathies are chronically disabling human disord ers caused by various genetic defects, including deletions, single site mut ations, and duplications in the respective myelin genes, We have shown in a mouse model of one distinct hereditary demyelinating neuropathy (heterozyg ous PO-deficiency, PO+-) that an additional null mutation in the recombinat ion activating gene-1 (RAG-1--) leads to a substantially milder disorder, i ndicating a disease modifying role of T-lymphocytes. In the present study, we addressed the role of lymphocytes in the mouse model by reconstituting b one marrow of PO+-/RAG-1-- mice with bone marrow from immunocompetent wild- type mice, We compared the pathology and nerve conduction in double mutant mice (PO+-/RAG-1-- on a C57BL/6 background) with that in double mutants aft er receiving a bone marrow transplant. We found that the milder demyelinati on seen in the lymphocyte-deficient PO+-/RAG-1-- mutants was reverted to th e 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 an d may open new avenues to ameliorate human hereditary neuropathies by explo iting immunosuppressive treatments.