Persistence of clonal T‐cell expansions following high‐dose chemotherapy and autologous peripheral blood progenitor cell rescue

Protheroe, Andrew; Pickard, C.; Johnson, Peter; Craddock, Tina; Shefta, Jahan; Short, Kath; Lancaster, F.; Selby, Peter J.; Henwood, Judy; Boylston, Arthur W.

doi:10.1111/j.1365-2141.2000.02427.x

Cited by 6 publications

(4 citation statements)

References 47 publications

(40 reference statements)

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“…Additionally, expansion of mature specific T cells is taking place particularly in the CD4 + subset, which generally exhibited increased cytokine and proliferation response even without Ag re-stimulation. In accordance with these findings, both clonal T-cell expansion and regeneration of T-cell receptor repertoire have been demonstrated after HD and stem cell transplantation by use of T-cell receptor analyses [32].…”

supporting

confidence: 63%

Antigen‐Specific T‐Cell Immunity in Multiple Myeloma Patients is Restored Following High‐Dose Therapy: Implications for Timing of Vaccination

2007

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The present study analyses the influence of high‐dose chemotherapy (HD) and autologous stem cell transplantation on natural and vaccine induced specific immunity in multiple myeloma patients. Peripheral blood was collected from six multiple myeloma (MM) patients at serial time points in connection with treatment and during a follow‐up period of 3 months. T‐cell response to cytomegalovirus (CMV), varicella zoster virus (VZV) and tetanus toxoid (TT) was determined by flow cytometry analysis for CD69, TNFα, IFNγ, IL‐4 expression and cell proliferation. At diagnosis and prior to induction chemotherapy TNFα expressing T cells in 5/6 patients were found specific for CMV, 3/6 for VZV and 4/6 for TT. Serial analyses during treatment conclude impaired immune response, however, 3 months post‐transplantation all but one patient had regained cytokine expressing CD8+ T cells specific for CMV, VZV and TT. The highest percentages of cytokine responding T cells were observed after stimulation with CMV antigen. A striking observation was the low cytokine reactivity (close to zero) measured in G‐CSF mobilized blood at the time of leukapheresis. In spite of a general reduction of the CD4/CD8 ratio following transplantation, recovery of antigen specific CD4+ T cells reactivity generally occurred prior to CD8+ recovery and often to a higher level. In conclusion, the study demonstrates that natural as well as vaccine induced specific immunity present prior to HD was regained after stem cell transplantation, hence identifying a possible window for future vaccination trials.

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supporting

confidence: 63%

Antigen‐Specific T‐Cell Immunity in Multiple Myeloma Patients is Restored Following High‐Dose Therapy: Implications for Timing of Vaccination

2007

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“…In accordance with these findings, clonal T cell expansion and regeneration of T cell receptor repertoire have been demonstrated after HD and stem cell transplantation by use of T cell receptor analyses. 35 In conclusion, this preliminary study demonstrates that specific immunity induced prior to HD can resist the treatment and reappear after transplantation. A larger series of patients is, however, necessary to draw definitive conclusions.…”

Section: Discussionmentioning

confidence: 93%

Impact of high-dose chemotherapy on antigen-specific T cell immunity in breast cancer patients. Application of new flow cytometric method

Svane

Nikolajsen

Hansen

et al. 2002

Bone Marrow Transplant

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Summary:The present study analyses the influence of high-dose chemotherapy (HD) and autologous stem cell transplantation on natural and vaccine-induced specific immunity in breast cancer patients. Peripheral blood was collected from five breast cancer patients at serial time points in connection with treatment and in a follow-up period of 1 year. The frequencies of CD8 ؉ and CD4 ؉ T cells responsive to cytomegalovirus (CMV), varicella zoster virus (VZV), and tetanus in antigen-activated whole blood were determined by flow cytometric analysis of CD69, TNF␣, IFN␥ and IL-4 expression. Mononuclear cells were labelled with PKH26 dye and the CMV, VZV, and tetanus toxoid-specific proliferation of T cell subpopulations was analysed by flow cytometry. In none of the patients did the treatment result in loss of overall T cell reactivity for any of the antigens. Prior to chemotherapy 5/5 patients possessed TNF␣ expressing T cells specific for CMV, 4/5 for VZV, and 3/5 for tetanus. One year after stem cell transplantation all patients possessed TNF␣ expressing T cells specific for CMV, VZV and tetanus. The highest percentages of cytokineresponding T cells were seen after stimulation with CMV antigen. In general, the lowest reactivity (close to zero) was measured in G-CSF-mobilised blood at the time of leukapheresis. In spite of a continuously reduced CD4 to CD8 ratio after transplantation, recovery of CD4 ؉ T cells usually occurred prior to CD8 ؉ recovery and often to a higher level. The study demonstrates that natural as well as vaccine-induced specific immunity established prior to HD can be regained after stem cell transplantation. These data indicate that introduction of a preventive cancer vaccination in combination with intensive chemotherapy may be a realistic treatment option. High-dose chemotherapy (HD) has been used as an adjuvant treatment for breast cancer patients with a high risk of disease recurrence. The dose-intensive regimen profoundly impairs the immune function, especially cell mediated functions, as indicated by several reports describing both qualitative and quantitative T cell imbalances, as well as defects in the proliferative response of T cells to common activators. [1][2][3][4][5][6][7] The aim of this study was to determine the influence of HD and autologous peripheral blood stem cell transplantation (PBSCT) on natural and vaccine-induced memory T cell immunity. For this purpose a prospective study of breast cancer patients treated with HD was carried out. Qualitative and quantitative evaluation of the cellular immune system were performed in connection with treatment and in a follow-up period of 1 year. The frequencies of cytomegalovirus (CMV), varicella zoster virus (VZV) and tetanus-responsive CD8 ϩ and CD4 ϩ subpopulations of T lymphocytes were analysed in antigen (Ag)-activated whole blood and determined by flow cytometric analysis. [8][9][10][11][12][13] Analyses of the specific immune reactivity of cancer patients undergoing treatment with HD impart knowledge about the impact of intensive ...

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“…Identical CDR3 region sequences were detected in post‐transplant blood T cells as well as the bone marrow (Gaschet et al , 1995). In some patients, the same TCR‐BV sequences of clonal TCR‐BV families were identified in peripheral blood before and after high‐dose therapy, providing evidence that the overwhelming majority of T cells in these expansions arise from mature lymphocytes (Protheroe et al , 2000). One may thus speculate that the reconstitution of the TCR‐BV repertoire may originate from mature lymphocytes, especially memory T cells.…”

Section: Discussionmentioning

confidence: 88%

Reconstitution of the T‐cell repertoire following treatment with alemtuzumab (anti‐CD52 monoclonal antibody) in patients with B‐cell chronic lymphocytic leukaemia

et al. 2006

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SummaryIn this pilot study, T-cell receptor B-variable (TCR-BV) gene usage in CD4 and CD8 T cells was assessed, by real-time polymerase chain reaction, as well as complementarity-determining region 3 (CDR3)-length polymorphism, before and after therapy in five patients with B-cell chronic lymphocytic leukaemia who received alemtuzumab (anti-CD52 monoclonal antibody) as first-line therapy. A decline in expression of most BV family genes in both CD4 and CD8 T cells was observed after alemtuzumab treatment, which was followed by a gradual increase in most BV families during long-term followup. After treatment, CDR3-length polymorphism showed an even more restricted pattern in CD4 T cells compared with pretreatment, with a shift towards a monoclonal/oligoclonal pattern. The clonally restricted pattern was significantly reduced in CD4 (P < 0AE01) but not in CD8 T cells. This was followed by a gradual increase in the number of peaks within the CDR3 region of the different TCR-BV families, i.e. a polyclonal repertoire, during long-term follow-up. A restricted CDR3 pattern became even more restricted after treatment, but normalised during unmaintained follow-up. These results indicate that perturbations in the T-cell alterations following alemtuzumab are complex and include not only changes in CD4/CD8 Tcell numbers but also a highly restricted T-cell repertoire especially in CD4 T cells.

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Persistence of clonal T‐cell expansions following high‐dose chemotherapy and autologous peripheral blood progenitor cell rescue

Cited by 6 publications

References 47 publications

Antigen‐Specific T‐Cell Immunity in Multiple Myeloma Patients is Restored Following High‐Dose Therapy: Implications for Timing of Vaccination

Antigen‐Specific T‐Cell Immunity in Multiple Myeloma Patients is Restored Following High‐Dose Therapy: Implications for Timing of Vaccination

Impact of high-dose chemotherapy on antigen-specific T cell immunity in breast cancer patients. Application of new flow cytometric method

Reconstitution of the T‐cell repertoire following treatment with alemtuzumab (anti‐CD52 monoclonal antibody) in patients with B‐cell chronic lymphocytic leukaemia

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