Immune reconstitution following haematopoietic stem cell transplantation

Stem cell transplantation is characterized by a subsequent period of immune deficiency, the duration and severity of which varies according to graft manipulation, choice of graft type (donor and source), development of graft-versus-host disease and level of residual thymic activity. This results in significant morbidity and mortality. Supportive therapies have advanced considerably leading to improved outcomes of infective episodes. However, disease relapse remains a considerable obstacle to improvement in overall outcomes. An increased understanding of the role of the immune system in preventing relapse, particularly in the allogeneic setting, has highlighted the importance of the reconstitution process. Successful application of some of the newer therapeutic strategies, such as tumour vaccination approaches, may depend critically on reconstitution of functional immune reactivity. In addition, the development of assays to measure recovery of antigen-specific immunity may allow further refinement of targeted therapies. This article reviews current knowledge of the reconstitution process. The escalation in doses of cytoreductive therapy that have characterized the development of haematopoietic stem cell transplantation (HSCT) protocols results in profound and long-lasting perturbations in immune response. Whilst early recovery of innate immunity [myeloid series and natural killer (NK) cells] results in reconstitution of protective immunity against many bacterial pathogens, both the absolute levels and function of T and B lymphocytes remain abnormal for many months, resulting in prolonged susceptibility to viral pathogens. More recently, the recognition that dose escalation alone does not eradicate the malignancy in many cases and that an associated immune-mediated graft-versus-malignancy effect may be equally important has led to the development of reduced intensity and non-myeloablative conditioning regimens, which aim to reduce the toxicity of the procedure by substituting more immunosuppressive agents in place of the myelosuppressive components of the original regimens. The influence of these developments on the tempo and characteristics of immune repertoire reconstitution are only just becoming evident. Incorporation of T-cell depletion, choice of graft type (both donor and source), development of graft-versus-host disease (GvHD) and level of residual thymic activity can all influence aspects of the reconstitution process. In addition, recent developments in the tools that are available for monitoring the reconstitution of these processes are providing new insights, particularly into the recovery of specific T-cell subsets. There are significant differences between the patterns of immune reconstitution following autologous and allogeneic transplants, relating both to the genetic and immunological disparity between donor and recipient in the latter, and to the influence of the immunosuppressive drugs employed to address these differences. These agents interfere both with quantitative and qualitative aspects of immune recovery. This review focuses on recent advances in the understanding of immune reconstitution in the allogeneic setting. Reference is made to autologous SCT only where it aids in the illustration of general principles, and for more comprehensive reviews the reader is referred elsewhere (Guillaume et al, 1999; Porrata et al, 2001).