CD4+ T Cell Dependent B Cell Recovery and Function After Autologous Hematopoietic Stem Cell Transplantation

Abstract

IntroductionHigh-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) represents a standard treatment regime for multiple myeloma (MM) patients. Common and potentially fatal side effects after auto-HSCT are infections due to a severely compromised immune system with hampered humoral and cellular immunity. This study delineates in depth the quantitative and functional B cell defects and investigates underlying extrinsic or intrinsic drivers.MethodsPeripheral blood of MM patients undergoing high-dose chemotherapy and auto-HSCT (before high-dose chemotherapy and in early reconstitution after HSCT) was studied. Absolute numbers and distribution of B cell subsets were analyzed ex vivo using flow cytometry. Additionally, B cell function was assessed with T cell dependent (TD) and T cell independent (TI) stimulation assays, analyzing proliferation and differentiation of B cells by flow cytometry and numbers of immunoglobulin secreting cells in ELISpots.ResultsQuantitative B cell defects including a shift in the B cell subset distribution occurred after auto-HSCT. Functionally, these patients showed an impaired TD as well as TI B cell immune response. Individual functional responses correlated with quantitative alterations of CD19+, CD4+, memory B cells and marginal zone-like B cells. The TD B cell function could be partially restored upon stimulation with CD40L/IL-21, successfully inducing B cell proliferation and differentiation into plasmablasts and immunoglobulin secreting cells.ConclusionQuantitative and functional B cell defects contribute to the compromised immune defense in MM patients undergoing auto-HSCT. Functional recovery upon TD stimulation and correlation with CD4+ T cell numbers, indicate these as extrinsic drivers of the functional B cell defect. Observed correlations of CD4+, CD19+, memory B and MZ-like B cell numbers with the B cell function suggest that these markers should be tested as potential biomarkers in prospective studies.

Progress and prospect of ASCT combined with CAR-T therapy in the treatment of multiple myeloma

“… 21 The function reconstruction of B lymphocytes still needs the assistance of T cells. 22 Therefore, the number and functional recovery of T cells determine the effectiveness of immune reconstitution; people began to vigorously use T cells to fight myeloma, including immunocheck point inhibitors, bispecific antibodies, and CAR-T cells. 12 …”

The shifting roles and toxicities of cellular therapies in B‐cell malignancies

“…B‐cell populations are restored via hematopoietic stem cell production and presence of B cells in the peripheral graft capable of proliferation, although small contributions from host B‐cell lymphocytes surviving conditioning chemotherapy also occur. Marked reductions in peripheral blood B‐cell populations occur immediately post‐ASCT and are similar across conditioning regimens and diseases (non‐Hodgkin lymphoma vs. myeloma), even in CD34‐selected grafts which may contain fewer T lymphocytes 43,44 . In myeloma ASCT, early B‐cell populations within the first 30 days are both quantitatively depleted but also functionally less able to respond to antigens.…”

“…In myeloma ASCT, early B‐cell populations within the first 30 days are both quantitatively depleted but also functionally less able to respond to antigens. Loss of important T‐cell interactions to activate B cells also drives loss of function in this early period 44 . B‐cell recovery typically follows a pattern of maturation observed in neonatal B‐cell development 45 .…”