Renewing the T cell repertoire to arrest autoimmune aggression

There is now evidence that high-dose immune ablation and autologous hematopoietic stem cell transplantation in humans triggers a reconstitution program that leads to the comprehensive renewal of the T cell repertoire. We argue here that several features of this program help to explain how autologous hematopoietic stem cell transplantation can induce long-term clinical remission from organ-specific-, as well as systemic, autoimmune diseases. We propose a model envisioning a coordinated sequence of events, rebuilding an immune system that is competent against infection but that is substantially reconfigured in a way that is less likely to redevelop autoimmunity. There is now evidence that high-dose immune ablation and autologous hematopoietic stem cell transplantation in humans triggers a reconstitution program that leads to the comprehensive renewal of the T cell repertoire. We argue here that several features of this program help to explain how autologous hematopoietic stem cell transplantation can induce long-term clinical remission from organ-specific-, as well as systemic, autoimmune diseases. We propose a model envisioning a coordinated sequence of events, rebuilding an immune system that is competent against infection but that is substantially reconfigured in a way that is less likely to redevelop autoimmunity. a multi-step treatment consisting of (i) collection of auto-HSCs from the patient, either via bone marrow harvest or by chemotherapy (cyclophosphamide, granulocyte colony-stimulating factor or both) to mobilize stem cells out of the bone marrow into the peripheral circulation, followed by leukapheresis to collect them; (ii) optional graft processing to enrich stem cells in the hematopoietic graft (usually CD34+ selection); (iii) immunoablative conditioning (various regimens with combinations of cytotoxic drugs and monoclonal antibodies sometimes associated with radiotherapy); (iv) hematopoietic rescue by reinfusion of the autologous graft; and (v) optional in vivo T cell purging; this consists of attempting to kill the mature T cells contaminating the hematopoietic graft (particularly when this is not manipulated to enrich for stem cells) after they have been reinfused in the body, and is typically achieved with anti-thymocyte globulin administered to the patient in the days immediately following stem cell infusion. one of the homeostatic mechanisms that act to control the size and composition of the mature T cell pool. Homeostatic proliferation occurs most prominently as a consequence of peripheral T cell depletion in response to homeostatic factors that include the cytokine IL-7 and signals originating from antigen–MHC ligands. the limited proliferative capacity of cells that have undergone extensive replication and is a consequence of cell division (not duration of quiescent cell survival). In human T cells, replicative senescence has been associated with a CD28−CD57+ phenotype, reduced telomere length and susceptibility to apoptosis. In the context of chronic antigenic stimulation, replicative senescence has been termed clonal exhaustion. the effect of size constraint on the memory T cell pool, resulting in competition for ‘space’ between memory cells. Attrition was first shown by the observation that viral infections cause a loss in memory responses to previously encountered viruses. In essence, pre-existing memory cells have to be sacrificed to make room for new ones. Large clonal expansions of memory cells during re-encounter of reactivated viruses after HSCT could limit the space available for all other specificities. a T cell that has undergone full maturation in the thymus and has been exported to the peripheral circulation and lymphoid organs but has not proliferated in the periphery. It can be identified with phenotypic markers but the ‘gold standard’ for quantification of RTEs relies on measuring TREC levels. TRECs are episomal DNA circles generated as byproducts of intrathymic TCR rearrangement. TRECs are not replicated and are therefore diluted at each round of cell division in the periphery. RTEs have high TREC levels. the volumetric enlargement and functional reactivation of the thymus following lymphoid depletion. It is rapid and prominent in children, and is delayed and reduced in older adults. The reappearance and increase in naïve cells in the peripheral circulation after HSCT is correlated with thymic rebound.