Severe and long-lasting disruption of T-cell receptor diversity in human myeloma after high-dose chemotherapy and autologous peripheral blood progenitor cell infusion

Vaccine-based strategies are currently under investigation as a means of in ducing tumour-specific immune responses and improving the clinical outcome of multiple myeloma (MM) patients in remission after high-dose chemotherapy and peripheral blood progenitor cell (PBPC) infusion. The immune competenc e of these patients was investigated by determining the overall diversity o f the T-cell receptor (TCR) repertoire in the peripheral blood (PB) and bon e marrow (BM). The average time after transplantation was 13 months. The cl onality and reciprocal usage of BV gene segments (TCRBV repertoire) was est imated at the cDNA level and membrane protein expression. The TCRBV reperto ire of MM was severely disrupted compared with age-matched normal donors. O n average, one-third of the total repertoire in both the PB and the BM cons isted of T cells expressing oligoclonal TCR beta transcripts. Flow cytometr y showed an increased frequency of abnormally expanded BV subfamilies at bo th sites. BV expansions were predominantly CD8(+) and had the phenotype of antigen-experienced memory T cells as well as T cells with the naive phenot ype. Oligoclonality was not restricted to phenotypically expanded BV subfam ilies, but also involved normally represented BV subfamilies. The TCR reper toire of MM in remission was then compared with monoclonal gammopathy of un determined significance (MGUS) and MM patients at diagnosis. The degree of TCR diversity was similar in age-matched normal donors and MGUS, but progre ssively decreased from MGUS to MM at diagnosis and then to MM in remission. These data indicate that: (1) there is a long-lasting and severe disruptio n of TCR diversity after high-dose chemotherapy and PBPC infusion, and (2) the extent of TCR disruption may affect the clinical outcome of vaccine-bas ed strategies delivered at the stage of minimal residual disease.