Assessment of thymic output in adults after haematopoietic stemcell transplantation and prediction of T-cell reconstitution

Summary:Positively selected CD34 + hematopoietic stem cells from unrelated donors (UD-HSCT) have been successfully transplanted, but little is known about immune reconstitution in this setting. Here we report a prospective comparison of immune reconstitution in recipients of UD-HSCT and of unmanipulated bone marrow from matched sibling donors (MSD-BMT). T-cell reconstitution occurred more than 100 days later in the UD-HSCT than in the MSD-BMT group. The first T cells after UD-HSCT were almost exclusively CD45RO + HLA-DR + , whereas early-emerging T cells after MSD-BMT more frequently expressed CD62L, CD28, and CD25. In both groups, numbers of CD45RA + naive T cells increased after 180 days. After UD-HSCT, the T-cell-receptor (TCR)-repertoire was severely skewed and showed significantly reduced diversity during the first year, but only minor abnormalities were seen after MSD-BMT. TCR-diversity increased simultaneously with the number of naive T cells. In both groups, we observed transient expansions of cd T cells. B cells were reconstituted more rapidly in UD-HSCT than in MSD-BMT recipients, whereas the rapidity of NK-cell reconstitution was similar in the two groups. In summary, T-cell reconstitution was slower after UD-HSCT than after MSD-BMT because of the delayed recovery of early memory-type T cells with reduced TCR-diversity, whereas naive T-, NK-, and B cells were reconstituted similarly in the two groups.

Section: Discussionmentioning

confidence: 80%

A prospective comparison of immune reconstitution in pediatric recipients of positively selected CD34+ peripheral blood stem cells from unrelated donors vs recipients of unmanipulated bone marrow from related donors

Eyrich

Leiler

Lang

et al. 2003

“…127 Such thymic damage has been assessed by measuring TREC or T-cell rearrangement excision circles in thymic emigrants 128 and GVHD is associated with decreases in TREC-containing thymocytes. 129 GVHD seems to adversely affect all levels of Tcell function, from delaying T-cell ontogeny 75 and limiting TCR diversity 82 to impairing cytokine production in reconstituted T cells.…”

Section: Mechanisms Of Immune Effector Dysfunction and Their Implicatmentioning

confidence: 99%

Immune restoration following hematopoietic stem cell transplantation: an evolving target

Auletta

Lazarus

2005

Summary:Hematopoietic stem cell transplantation (HSCT) is the definitive cure for many malignant and nonmalignant diseases. However, delays in immune reconstitution (IR) following HSCT significantly limit the success of transplantation and increase the risk for infection and disease relapse in the transplant recipient. Therefore, ways to measure and to manipulate immune recovery following HSCT are emerging and their success depends directly upon an enhanced understanding for the underlying mechanisms responsible for reconstituted immunity and hematopoiesis. Recent discoveries in the activation, function, and regulation of dendritic cell (DC), natural killer (NK) cell, and T-lymphocyte subtypes have been critical in developing immunotherapies used to prevent graft-versushost disease and to enhance graft-versus-leukemia. For example, regulatory T cells that induce tolerance and NK receptor-tumor ligand disparities that result in tumor lysis are being used to minimize GVHD and tumor burden, respectively. Furthermore, expansion and modulation of immune effector cells are being used to augment hematopoietic and immune recovery and to decrease transplantrelated toxicity in the transplant recipient. Specifically, DC expansion and incorporation into antitumor and antimicrobial vaccines is fast approaching application into clinical trials. This paper will review our current understanding for IR following HSCT and the novel ways in which to restore immune function and decrease transplantrelated toxicity in the transplant recipient. Bone Marrow Transplantation (2005) 35, 835-857.

“…This has been documented using phenotypic markers of thymic emigrants (e.g. CD45RA and CD62L expression on CD4 þ cells), 15 as well as using newer techniques used to measure thymic function, including measurement of T-cell receptor excision circles 16 and T-cell receptor repertoire analysis. 17 Thymic function is limited by age-related declines in thymic function, and thymic toxicity induced by cytotoxic therapy, radiation or GVHD.…”

Section: T-cell Immune Reconstitutionmentioning

confidence: 99%

Immune reconstitution following hematopoietic progenitor cell transplantation: challenges for the future

Fry

Mackall

2005

Summary:Successful hematopoietic progenitor cell transplantation requires rapid and complete transfer of the donor hematopoietic and immune systems to the host. Whereas the uncontrolled transfer of a nontolerant donor immune system results in GVHD in many cases, strategies which diminish GVHD also diminish immune reconstitution. Thus, the reliable, rapid and safe transfer of immunity from donor to host remains a major challenge for the field. Advances in the understanding of the biology of immune reconstitution have elucidated that thymic-dependent immune reconstitution can restore global immunity, but is especially vulnerable to toxicities associated with transplant. Alternatively, homeostatic peripheral expansion can be exploited for targeted immunity toward pathogens and tumors, but is difficult to manipulate without exacerbating GVHD risk. New translatable strategies are needed to safely augment one or both of these pathways in the setting of allogeneic hematopoietic progenitor cell transplantation. Bone Marrow Transplantation (2005) 35, S53-S57.