Concise Review: Boosting T-Cell Reconstitution Following Allogeneic Transplantation—Current Concepts and Future Perspectives

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for a large number of malignant and nonmalignant (inherited) diseases of the hematopoietic system. Nevertheless, non‐HLA identical transplantations are complicated by a severe T‐cell immunodeficiency associated with a high rate of infection, relapse and graft‐versus‐host disease. Initial recovery of T‐cell immunity following HSCT relies on peripheral expansion of memory T cells mostly driven by cytokines. The reconstitution of a diverse, self‐tolerant, and naive T‐cell repertoire, however, may take up to 2 years and crucially relies on the interaction of T‐cell progenitors with the host thymic epithelium, which may be altered by GvHD, age or transplant‐related toxicities. In this review, we summarize current concepts to stimulate reconstitution of a peripheral and polyclonal T‐cell compartment following allogeneic transplantation such as graft manipulation (i.e., T‐cell depletion), transfusion of ex vivo manipulated donor T cells or the exogenous administration of cytokines and growth factors to stimulate host‐thymopoiesis with emphasis on approaches which have led to clinical trials. Particular attention will be given to the development of cellular therapies such as the ex vivo generation of T‐cell precursors to fasten generation of a polyclonal and functional host‐derived T‐cell repertoire. Having been tested so far only in preclinical mouse models, clinical studies are now on the way to validate the efficacy of such T‐cell progenitors in enhancing immune reconstitution following HSCT in various clinical settings. stem cells translational medicine 2019;00:1–8

Co‑transplantation of tonsil‑derived mesenchymal stromal cells in bone marrow transplantation promotes thymus regeneration and T cell diversity following cytotoxic conditioning

“…In the thymus-dependent recovery of T cells, crosstalk between thymic stromal cells and developing thymocytes must be regulated. However, this regulation can be restricted by damaged or altered thymic niches due to pre-conditioning regimens, infections, GVHd, or recipient age (5,6). The function of thymic epithelial cells (TEcs) in T cell development is related to the development of immature thymocytes into competent T cells that respond to foreign antigens, but are self-tolerant.…”

Evaluating Thymic Function After Human Hematopoietic Stem Cell Transplantation in the Personalized Medicine Era

“…The thymus is a sensitive organ and suffer considerable damage during most HSCT protocols by the conditioning regimen and corticoids, and also post-transplant by infections and GvHD, leading to incomplete T-cell reconstitution and increased risk of infection and mortality ( Figures 1A,D) (2). Regenerative therapies are under investigation to avoid thymic injury and to boost thymic output when appropriate ( Figure 1E).…”

“…Enhancing thymic function leading to efficient T-cell reconstitution might be a promising route for future HSCT. In this regard, several strategies have been investigated yet so far only few have been successfully translated to the clinic ( Figure 1E) (2).…”

“…Its clinical outcome relies on a successful immune recovery, particularly an optimal T-cell reconstitution. Following HSCT, innate immune cells recover in the initial weeks to months post-HSCT, while the T-cell pool recovery is accomplished through thymic-independent homeostatic proliferation of donor-derived mature T-cells in the 1st year (2). Thereafter, the thymic-dependent de novo generation of naïve T-cells from donor hematopoietic stem cells (HSCs) play an essential role for immune restoring in a process that can take years and is responsible for the full restoration of TCR specificities (3).…”

Considerations in Preparative Regimen Selection to Minimize Rejection in Pediatric Hematopoietic Transplantation in Non-Malignant Diseases

“…The expansion of alloreactive T cells will ultimately result in varying degrees of GVHD, and will have a substantial impact on both long term toxicity and treatment related mortality. Simultaneously, the newly reconstituting immune system is striving to achieve a protective state against infections, building new B and T cell repertoires while priming to new antigens (38,(86)(87)(88)(89)(90). Further complicating this process is the impact specific preparative regimen agents may have on the newly emerging lymphocyte population.…”