B-Cell Reconstitution After Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

Abstract

Background and ObjectivesAutologous hematopoietic stem cell transplantation (aHSCT) is increasingly used to treat aggressive forms of multiple sclerosis (MS). This procedure is believed to result in an immune reset and restoration of a self-tolerant immune system. Immune reconstitution has been extensively studied for T cells, but only to a limited extent for B cells. As increasing evidence suggests an important role of B cells in MS pathogenesis, we sought here to better understand reconstitution and the extent of renewal of the B-cell system after aHSCT in MS.MethodsUsing longitudinal multidimensional flow cytometry and immunoglobulin heavy chain (IgH) repertoire sequencing following aHSCT with BCNU + Etoposide + Ara-C + Melphalan anti-thymocyte globulin, we analyzed the B-cell compartment in a cohort of 20 patients with MS in defined intervals before and up to 1 year after aHSCT and compared these findings with data from healthy controls.ResultsTotal B-cell numbers recovered within 3 months and increased above normal levels 1 year after transplantation, successively shifting from a predominantly transitional to a naive immune phenotype. Memory subpopulations recovered slowly and remained below normal levels with reduced repertoire diversity 1 year after transplantation. Isotype subclass analysis revealed a proportional shift toward IgG1-expressing cells and a reduction in IgG2 cells. Mutation analysis of IgH sequences showed that highly mutated memory B cells and plasma cells may transiently survive conditioning while the analysis of sequence cluster overlap, variable (IGHV) and joining (IGHJ) gene usage and repertoire diversity suggested a renewal of the late posttransplant repertoire. In patients with early cytomegalovirus reactivation, reconstitution of naive and memory B cells was delayed.DiscussionOur detailed characterization of B-cell reconstitution after aHSCT in MS indicates a reduced reactivation potential of memory B cells up to 1 year after transplantation, which may leave patients susceptible to infection, but may also be an important aspect of its mechanism of action.

From bedside to bench: how existing therapies inform the relationship between Epstein–Barr virus and multiple sclerosis

“…The London study group demonstrated detectable viraemia in 80% of PwMS between day 23 and 46 post‐AHSCT 55 . A Swiss study identified viraemia in 2 of 20 PwMS undergoing AHSCT for MS; however, 90% of the cohort had been treated with B cell therapy prior to transplant, which may have contributed to the low rate of post‐transplant viraemia 56 . EBV DNAemia is common in patients treated with Alemtuzumab as a conditioning agent during allogenic HSCT 57 .…”

“… 55 A Swiss study identified viraemia in 2 of 20 PwMS undergoing AHSCT for MS; however, 90% of the cohort had been treated with B cell therapy prior to transplant, which may have contributed to the low rate of post‐transplant viraemia. 56 EBV DNAemia is common in patients treated with Alemtuzumab as a conditioning agent during allogenic HSCT. 57 No data are available for treatment with Alemtuzumab alone, or with Cladribine.…”

Haematopoietic Stem Cell Transplantation for the Treatment of Multiple Sclerosis: Recent Advances

“…In another recent study, longitudinal multidimensional cytometry and immunoglobulin heavy chain (IgH) repertoire sequencing were used to investigate the B cell immune reconstitution in 20 MS patients receiving AHSCT with BEAM-ATG regimen and anti-CD20 treatment before and 1, 3, 6 and 12 months after AHSCT and compared to HC [ 10 •]. B-lymphocyte number recovered at 3 months and remained increased at 1 year post AHSCT.…”

The Place of Immune Reconstitution Therapy in the Management of Relapsing Multiple Sclerosis in France: An Expert Consensus

“…The application of aHSCT involves mobilisation of haematopoietic stem cells (HSCs) and their progenitor cells, and ablation of lymphocytes using chemotherapy including cyclophosphamide and granulocyte colony stimulating factor. HSCs are harvested and subsequently reinfused, leading to reconstitution of the immune system and (in responders) suppression of MS relapses [ 24 , 86 ].…”