ANALYSIS OF REARRANGED IMMUNOGLOBULIN HEAVY-CHAIN VARIABLE REGION GENES OBTAINED FROM A BONE-MARROW TRANSPLANT (BMT) RECIPIENT

Haematopoietic stem cell transplantation has been used for the treatme nt of many different malignant and non-malignant diseases. The immune system of transplant recipients must be regenerated from the transplan t inoculum, and it Is not surprising that many transplant recipients a re deficient in generating specific antibody responses to exogenous st imuli, This B cell immunodeficiency in these patients is associated wi th clinically significant infections, although the underlying mechanis m remains unknown. We have previously shown that the pattern of usage of V-H genes was similar between healthy subjects and BMT recipients, indicating that the immunodeficiency was not due. to a dramatic imbala nce in V-H utilization. However, motif-specific hybridization analysis indicated that the accumulation of somatic mutations was much greater among rearrangements in controls than in BMT recipients, The failure of BMT recipients to accumulate somatic mutations in rearranged V-H ge nes correlates with an absence of IgD(-) B cells, and is consistent wi th a defect in antigen-driven B cell responses. In the current study, which extends those findings, we have determined the nucleotide sequen ces of 68 heavy chain rearrangements from one patient as well as 39 re arrangements from a healthy control. Analysis of these sequences made possible a more precise definition of variable region configuration an d of the status of somatic mutation in this BMT recipient. The results validate the hybridization data and support the conclusion that, alth ough somatic hypermutation and, by inference, antigen-driven responses are detected in BMT recipients, they are deficient compared with heal thy subjects as late as 1 year after transplant.