Enhancing Immune Reconstitution: From Bench to Bedside

Abstract

INTRODUCTION Slow and incomplete reconstitution of cellular and humoral immunity has long been recognized as a weak link limiting the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Delayed posttransplantation reconstitution of the adaptive immune system is associated with increased infection, relapse, secondary malignancies, and overall mortality in recipients of an allo-HSCT [1,2]. In particular, reconstitution of the T cell compartment can take 1-2 years, and deficiencies in the T cell repertoire can persist even longer. Deficiencies in T cell reconstitution are dependent on patient age, conditioning regimen, use of in vitro or in vivo T cell depletion to decrease graft-versus-host disease (GVHD), HLA disparity between donor and recipient, and GVHD prophylaxis, as well as the occurrence of GVHD. T cell recovery after allo-HSCT occurs through 2 unrelated mechanisms: (1) peripheral expansion of infused donor T cells and, to a lesser extent, residual host T cells, and (2) de novo T cell development in the thymus. Peripheral expansion is associated with a narrow repertoire, whereas de novo T cell development can reconstitute a full T cell repertoire. However, damage from conditioning and GVHD, in combination with age-associated involution, results in poor posttransplantation thymic function. Consequently, this review takes a “bench-to-bedside” approach, evaluating strategies aimed at enhancing not only the peripheral expansion of the tumor and virus-specific immune response, but also the recovery of thymic function (Figure 1).