Jump-starting immune reconstitution after stem cell transplantation

Recipients of hematopoietic stem cell transplants (HSCT) are at high risk for opportunistic infection. Bacterial and certain fungal infections predominate during the immediate posttransplantation period when patients are neutropenic and have abnormal mucosal barriers. But HSCT recipients continue to be at risk for infections even after their neutropenia and mucositis have resolved. Particularly problematic are infections with cytomegalovirus (CMV) and Epstein-Barr virus, which is associated with the development of posttransplantation lymphoproliferative disease. The problem of immune deficiency is exacerbated by both graft-versus-host disease (GVHD) and procedures to remove mature T lymphocytes to prevent GVHD. Adoptive transfer of mature T lymphocytes as either T-cell clones or polyclonal mixtures of donor cells has been used to confer immunity to either specific pathogens or malignant cells. Adoptive transfer strategies are narrowed by the limited survival and narrow repertoire of antigenic recognition or effector functions of cloned antigen-specific T cells, while polyclonal donor lymphocyte infusions risk triggering GVHD.

The underlying lymphoid defects in HSCT recipients include defective lymphopoiesis, especially thymopoiesis, as well as immune dysregulation. Some of the factors that may restrict the ability of HSCs to reconstitute the immune system are the limited proliferation of HSCs or limitations on commitment to lymphoid lineages. In this issue, Arber and colleagues (page 421) describe a novel approach to immune reconstitution, using common lymphoid progenitors (CLPs). CLPs are a subset of committed progenitors with restricted ability to differentiate into T, NK, and B lymphocytes but not other hematopoietic lineages. Like HSCs, CLPs are prethymic, do not express T-cell receptors, and therefore have not been selected in the thymus for antigenic specificities that could cause GVHD. CLPs are highly proliferative but lack self-renewal capacity. Using fluorescence-based cell sorting to isolate different populations of donor progenitors, Arber et al transplanted either purified HSCs or a combination of HSCs and CLPs into irradiated mice. The mice receiving transplants did not develop GVHD, even when the donor cells were major histocompatibility complex (MHC)–mismatched with the recipients. The mice were challenged with experimental infection with murine cytomegalovirus (MCMV) soon after HSC transplantation. The mortality of HSCT recipients was reduced from nearly 90% to approximately 40% in the recipients of both HSCs and CLPs. The potency of CLPs was demonstrated in experiments showing that transplantation of 3000 CLPs was as protective as adoptive transfer of 10 000 000 lymph node cells. CLP transplantation altered the histopathology of the MCMV infection, resulting in greater inflammatory responses and less viral burden.

While the paper by Arber et al represents a landmark in efforts to improve immune reconstitution after HSC transplantation, a number of important and interesting questions remain. Since the CLPs can contribute to each lymphoid lineage, the exact effects of cotransplantation are likely to be complex. For example, CLPs also protected thymectomized mice from MCMV, suggesting that reconstitution of non-T cells is an important effect of CLP transplantation. The determinants of proliferation and differentiation of CLPs after transplantation need to be elucidated. Translation of the murine experiments to clinical HSC transplantation will be a challenge. Like murine CLPs, CLPs are a rare subset of human marrow. Are they more common in other progenitor sources, for example, mobilized peripheral blood? In experimental transplantations, sufficient numbers of rare donor progenitors can be obtained simply by using multiple donors for each recipient. Since this is not practical in clinical transplantation, strategies to expand CLPs in vitro or in vivo may be necessary to achieve a clinically relevant dose of CLPs to enhance immune reconstitution. The work by Arber et al is also likely to lead to other studies of how committed progenitors can be used to rapidly reconstitute specific hematopoietic lineages.