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

Abstract

Summary. Vaccine-based strategies are currently under investigation as a means of inducing tumour-specific immune responses and improving the clinical outcome of multiple myeloma (MM) patients in remission after highdose chemotherapy and peripheral blood progenitor cell (PBPC) infusion. The immune competence of these patients was investigated by determining the overall diversity of the T-cell receptor (TCR) repertoire in the peripheral blood (PB) and bone marrow (BM). The average time after transplantation was 13 months. The clonality and reciprocal usage of BV gene segments (TCRBV repertoire) was estimated at the cDNA level and membrane protein expression. The TCRBV repertoire of MM was severely disrupted compared with agematched normal donors. On average, one-third of the total repertoire in both the PB and the BM consisted of T cells expressing oligoclonal TCRb transcripts. Flow cytometry showed an increased frequency of abnormally expanded BV subfamilies at both sites. BV expansions were predominantly CD81 and had the phenotype of antigen-experienced memory T cells as well as T cells with the naive phenotype. Oligoclonality was not restricted to phenotypically expanded BV subfamilies, but also involved normally represented BV subfamilies. The TCR repertoire of MM in remission was then compared with monoclonal gammopathy of undetermined significance (MGUS) and MM patients at diagnosis. The degree of TCR diversity was similar in age-matched normal donors and MGUS, but progressively 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 disruption of TCR diversity after high-dose chemotherapy and PBPC infusion, and (2) the extent of TCR disruption may affect the clinical outcome of vaccine-based strategies delivered at the stage of minimal residual disease.

Cytotoxic chemotherapy preceding apheresis of peripheral blood progenitor cells can affect the early reconstitution phase of naive T cells after autologous transplantation

“…26,27 Therefore, assuming that T cells with a naive phenotype contain the largest fraction of the TcR repertoire, 28 it could be speculated that the starting pool of mature T cells may provide a substantial lymphopoietic support to the severe disruption of TcR diversity in the early phase after HD-ChT. 29 The question remains as to whether high numbers of T cells in the grafts may confer not only more rapid T-cell reconstitution, but also better immune competence and perhaps overall prognosis. 30 In fact, following HD-ChT, patients are more susceptible to opportunistic infections and to reactivation of persistent virus after transplantation.…”

Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2 Concerted Action BMH4-CT98-3936

“…35 Recovery from transplantation and hematological remission are followed by restoration of the polyclonal TCR repertoire. 36,37 5. False-positive results: False-positive results are rare by Southern blot analysis and can generally be prevented by checking for underdigestion and by excluding polymorphic restriction sites.…”

Long-term follow-up of idiotype vaccination in human myeloma as a maintenance therapy after high-dose chemotherapy

“…19 We distinguished four CDR3 size distribution patterns: (1) normal, with a Gaussian distribution of BV-BC CDR3 fragments; (2) reactive, with one or more peaks above the normal Gaussian background; (3) deteriorated, in which the Gaussian distribution was replaced by two or more predominant peaks; and (4) single peak, with a prominent single peak. The TCRBV repertoire was evaluated in eight patients before vaccination, during vaccination, and 6 and 12 months after the last immunization.…”

“…Determination of the clonality and reciprocal usage of BV gene segments has shown that the TCR repertoire is severely disrupted in MM patients after high-dose chemotherapy and PBPC infusion. 19 On average, one-third consists of T cells expressing oligoclonal or abnormal TCRBV transcripts. 19 A progressive recovery of TCR diversity was observed following the start of vaccination, as shown by the increase of polyclonal and the decrease of abnormal TCRBV transcripts.…”