Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

The timely reconstitution and regain of function of a donor-derived immune system is of utmost importance for the recovery and long-term survival of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Of note, new developments such as umbilical cord blood or haploidentical grafts were associated with prolonged immunodeficiency due to delayed immune reconstitution, raising the need for better understanding and enhancing the process of immune reconstitution and finding strategies to further optimize these transplant procedures. Immune reconstitution post-HSCT occurs in several phases, innate immunity being the first to regain function. The slow T cell reconstitution is regarded as primarily responsible for deleterious infections with latent viruses or fungi, occurrence of graft-versus-host disease, and relapse. Here we aim to summarize the major steps of the adaptive immune reconstitution and will discuss the importance of immune balance in patients after HSCT.

Keywords: graft-versus-host disease; graft-versus-leukemia effect; hematopoietic stem cell transplantation; immune reconstitution; infection.

Figure 1

Overview of immune cell differentiation. The figure shows the different types of immune cells and their development from different precursors. The reconstitution of innate immunity occurs rapidly within 20–30 days after allogeneic HSCT while reconstitution of adaptive immunity is delayed following HSCT and can require up to 1 year. Natural killer (NK) cells, monocytes, granulocytes, and dendritic cells are derived from myelomonocytic progenitor cells. B and T cells differentiate from lymphoid progenitor cells and require specialized microenvironments in order to efficiently differentiate from primitive progenitors, and typically show delayed and incomplete recovery. Reprinted by permission from Macmillan Publishers Ltd.: Bone Marrow Transplantation (5), copyright (2005).

Figure 2

Time line of complications after allogeneic HSCT. The figure shows the most prevalent complications after HSCT according to the three phases of engraftment. Concomitant infectious complications consisting of bacterial, fungal, and viral infections are shown according to their occurrence as well as association with acute and chronic GvHD during different phases of follow-up: (1) pre-engraftment, (2) engraftment, and (3) post-engraftment phase. Abbreviations: CMV, cytomegalovirus; aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease.

Figure 3

Development of natural and induced regulatory T cells. Natural regulatory T cells (nTregs) are derived from the thymus and are characterized by the co-expression of CD4, high expression of CD25 and FoxP3, and are collectively represented as CD4⁺CD25⁺FoxP3⁺ Tregs. Induced or adaptive regulatory T cells (iTregs) are generated in the peripheral lymphoid organs in the presence of transforming growth factor beta (TGF-β) and interleukin-2 (IL-2).

Figure 4

Recovery of CMV-specific cytotoxic T lymphocytes after HSCT. Examples of reconstitution of CMV-specific cytotoxic T lymphocytes (CTLs) after HSCT for CMV-seropositive recipients transplanted from CMV-seropositive donors (R+/D+) (A) and CMV-seropositive recipients transplanted from CMV-seronegative donors (R+D−) (B) are shown. CMV–CTL numbers per microliter of whole blood (left y-axis) were plotted against the time after HSCT (days). The right y-axis shows the number of pp65-positive cells/400,000 leukocytes (detection of CMV-reactivation). The CMV R+D+ patient had a CMV-reactivation by day +39 and responded by an expansion of CMV–CTLs. No significant reconstitution of CMV–CTLs within the CMV R+D− patient was detected until day +100 despite the early CMV reactivation. Adapted from Ref. (136).