Long-term immune reconstitution and T cell repertoire analysis after autologous hematopoietic stem cell transplantation in systemic sclerosis patients

Abstract

The determinants of clinical responses after autologous hematopoietic stem cell transplantation (aHSCT) in systemic sclerosis (SSc) are still unraveled. We analyzed long-term immune reconstitution (IR) and T cell receptor (TCR) repertoire diversity in 10 SSc patients, with at least 6 years simultaneous clinical and immunological follow-up after aHSCT. Patients were retrospectively classified as long-term responders (A, n = 5) or non-responders (B, n = 5), using modified Rodnan’s skin score (mRSS) and forced vital capacity (FVC%). All patients had similar severe SSc before aHSCT. Number of reinjected CD34+ cells was higher in group B versus A (P = 0.02). Long-term mRSS fall >25% was more pronounced in group A (P = 0.004), the only to improve long-term FVC% >10% (P = 0.026). There was an overall trend toward increased of T cell reconstitution in group B versus A. B cells had a positive linear regression slope in group A (LRS = 11.1) and negative in group B (LRS = −11.6). TCR repertoire was disturbed before aHSCT and the percentage of polyclonal families significantly increased at long-term (P = 0.046), with no difference between groups. Despite improved skin score after aHSCT in all SSc patients, pretransplant B cell clonal expansion and faster post-transplant T cell IR in long-term non-responder/relapsing patients call for new therapeutic protocols guided by IR analysis to improve their outcome.

Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients

“…Relapsing disease post-AHSCT was defined by 1 of the following criteria: increase of the mRSS by 25% from best improvement, or decline in forced vital capacity by 10%, renal crisis, start of total parenteral nutrition, or restarting of immune suppressive or modulating medication, as previously described. 33,35 According to clinical response at long-term post-AHSCT, SSc patients were retrospectively classified as "responders" and "nonresponders." According to the European Group for Blood and Marrow Transplantation guidelines, 13 peripheral blood samples were collected at baseline and every 6 months until 36 months after transplantation for immune monitoring.…”

“…Persistent increase of Th1/Th2 ratios, 58 recovery of Treg function, 14 changes in thymic output, 19,33,59 and lower profibrotic serum cytokine levels 60 have been described. Several questions still remain, especially concerning the immunological determinants of clinical outcomes.…”

“…25,26 AHSCT aims to deplete the autoimmune repertoire and generate a new immune system, thereby reestablishing a state of autotolerance, already shown in multiple sclerosis, 27,28 systemic lupus erythematosus, 29,30 juvenile arthritis, 31 Crohn disease, 32 and SSc. 19,33 In SSc, we previously showed how posttransplant CD4 T-cell reconstitution correlates with long-term clinical response to AHSCT. 19,33 However, recovery of specific lymphocyte subpopulations, including those with regulatory functions, as well as thymic and bone marrow functions, and how they may be associated with clinical outcomes remain to be assessed.…”

“…19,33 In SSc, we previously showed how posttransplant CD4 T-cell reconstitution correlates with long-term clinical response to AHSCT. 19,33 However, recovery of specific lymphocyte subpopulations, including those with regulatory functions, as well as thymic and bone marrow functions, and how they may be associated with clinical outcomes remain to be assessed. Here, we analyzed the immunological profile and T-and B-cells immune reconstitution of SSc patients that underwent AHSCT.…”

Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases

“…6,[44][45][46] In conjunction with both prospective and registry studies, mechanistic studies have been progressively produced. [47][48][49][50] The recent publication of guidelines for studies of immune reconstitution studies and biobanking provides the necessary framework for further development of mechanistic studies. 51 More standardized approaches to immune monitoring should facilitate correlative studies with outcomes of HSCT and potentially enable biomarkers to be developed to assist with patient selection and treatments.…”