Challenges and Opportunities for Biomarkers of Clinical Response to AHSCT in Autoimmunity

Abstract

Autoimmunity represents a broad category of diseases that involve a variety of organ targets and distinct autoantigens. For patients with autoimmune diseases who fail to respond to approved disease-modifying treatments, autologous hematopoietic stem cell transplantation (AHSCT) after high-dose immunosuppressive therapy provides an alternative strategy. Although more than 100 studies have been published on AHSCT efficacy in autoimmunity, the mechanisms that confer long-term disease remission as opposed to continued deterioration or disease reactivation remain to be determined. In a phase II clinical trial, high-dose immunosuppressive therapy combined with autologous CD34+ hematopoietic stem cell transplant in treatment-resistant, relapsing-remitting multiple sclerosis (RRMS) resulted in 69.2% of participants achieving long-term remission through 60 months follow-up. Flow cytometry data from the 24 transplanted participants in the high-dose immunosuppression and autologous stem cell transplantation for poor prognosis multiple sclerosis (HALT-MS) trial are presented to illustrate immune reconstitution out to 36 months in patients with aggressive RRMS treated with AHSCT and to highlight experimental challenges inherent in identifying biomarkers for relapse and long-term remission through 60 months follow-up. AHSCT induced changes in numbers of CD4 T cells and in the composition of CD4 and CD8 T cells that persisted through 36 months in participants who maintained disease remission through 60 months. However, changes in T cell phenotypes studied were unable to clearly discriminate durable remission from disease reactivation after AHSCT, possibly due to the small sample size, limited phenotypes evaluated in this real-time assay, and other limitations of the HALT-MS study population. Strategies and future opportunities for identifying biomarkers of clinical outcome to AHSCT in autoimmunity are also discussed.

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

“…Our results confirmed findings about general immune reconstitution dynamics observed in other settings, namely diverging kinetics among major subsets in which innate immunity typically precedes adaptive immunity 42 and the differentially affected T-cell subsets leading to an inverted CD4/CD8 ratio during the first year after transplantation. 7,10,29 Naive T-cell subsets were still below normal levels up to 1 year after aHSCT, whereas early circulating B cells were dominated by transitional and naive phenotypes, as shown before in the context of HSCT. 27 Because interaction between primed CD4 + T cells and naive B cells is essential for B-cell activation and differentiation, the delayed regeneration of the CD4 + compartment may be a key factor in slowing down the recovery of MBC subsets.…”

Extensive intrathecal T cell renewal following hematopoietic transplantation for multiple sclerosis

“…Given that this association was not observed at month 12 after transplant, we did not expect to find an association between clinical outcome and diversification of the TCR repertoire in blood T cells at months 24 and 48 analyzed here. While none of our TCR repertoire analyses revealed associations with disparate long-term clinical outcomes, we accept the limitations of the study for identifying biomarkers of response as reported previously (13).…”

“…TCR repertoire diversity was analyzed using the Shannon entropy index in blood CD4 + and CD8 + T cells before therapy and at months 12, 24, and 48 after transplant. (B) Ratios of circulating CD4 + (top) and CD8 + (bottom) central memory (Tcm) and effector memory (Tem) to naive (Tn) cells were analyzed by flow cytometry, as previously reported (13). Filled triangles represent participants that met the primary endpoint for the HALT-MS study before month 60 after transplant, and open circles represent participants that stayed in remission from active MS until the last follow-up.…”

Haematopoietic Stem Cell Transplantation Results in Extensive Remodelling of the Clonal T Cell Repertoire in Multiple Sclerosis

“…While defining public pathogenic T-cell clones in MS has to date proved elusive, a consistent pattern of immuno-ablation and immune reconstitution of T-cell populations following AHSCT has been established (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Following administration of an immuno-ablative conditioning regimen there is a bimodal recovery of T-cell populations.…”