11. A broad T-cell repertoire diversity and an efficient thymic function indicate a favorable long-term immune reconstitution after cord blood stem cell transplantation.  Talvensaari K, Clave E, Douay C, Rabian C, Garderet L, Busson M, Garnier F, Douek D, Gluckman E, Charron D, Toubert A.  Blood. 2002;99:1458-1464.

This study was designed to evaluate T-cell reconstitution using combined approaches of phenotyping, analysis of alphabeta T-cell receptor (TCR) diversity, and assessment of ex vivo thymic function by measuring TCR rearrangement excision circles (TRECs). Ten patients who underwent CB transplantation for high-risk hematologic disorders were compared to a reference group of 19 age- and GVHD-matched patients who underwent transplantation with non-T cell-depleted bone marrow from an HLA-identical sibling donor. TREC values correlated with the relative number of naive T cells and with TCR repertoire polyclonality. During the first year after transplantation, TCR repertoires were highly abnormal and TREC values low in both groups. Notably, 2 years after transplantation onward TREC values as well as TCR diversity were higher in CB recipients than in recipients of bone marrow transplants. The authors state that their data indicate an efficient thymic regeneration pathway from CB lymphoid progenitors despite the low number of cells infused compared to bone marrow, arguing for a complete clinical immune recovery after CB transplantation.

12. T lymphocytes of recipient origin may contribute to the recovery of specific immune response toward viruses and fungi in children undergoing cord blood transplantation. Montagna D, Locatelli F, Moretta A, Lisini D, Previdere C, Grignani P, DeStefano P, Giorgiani G, Montini E, Pagani S, Comoli P, Maccario R. Blood. 2004;103:4322-9.

Cord blood lymphocytes are naïve cells, with low T-cell-mediated cytotoxic capacity and, in vitro, markedly reduced responsiveness to allogeneic stimuli in secondary mixed lymphocyte reaction. There are concerns that patients undergoing allogeneic cord blood transplantation (CBT) may not be able to recover an effective immune capacity early after transplantation. The aims of the study were to evaluate the ability of recipients of cord blood transplants to develop an in vitro immune response toward 2 widespread pathogens (CMV and Candida Albicans), both early and late after transplantation and to define the origin, either donor or patient, of T cells contributing to the immune response. The studies were performed in children given cord blood transplants from either an HLA-identical sibling or an unrelated donor. Proliferative capacity and frequency of antigen-specific T cells were evaluated; antigen-specific CD4(+) T-cell clones were also generated and characterized for T-cell receptor repertoire diversity, cytokine phenotype, and their origin (either from donor or patient). Results indicated that the majority of recipients developed a specific response to viral or fungal antigens early after transplantation. Antigen-specific T-cell clones of both donor and recipient origin contributed to the immune reconstitution. Antigen-specific T lymphocytes of recipient origin were detected in patients receiving a transplant from a relative, after a chemotherapy-based conditioning regimen, and who did not have GVHD. These studies document, at a clonal level, that after CBT recovery of either polyclonal or pauciclonal T-cell response toward widespread pathogens is prompt, with some patients benefiting from a contribution of recipient-derived cells. The authors further stated that their data support previously reported results indicating a post-CBT recovery of T-lymphocyte number and a response to polyclonal activators at least comparable to that observed in BMT recipients and characterized by a fully reconstituted TCR repertoire. However, all of the patients studied were children, most received a CBT from an HLA-identical sibling, and none developed GVHD; these factors may contribute to the prompt recovery of T-cell-mediated antigen-specific immune responses.

13. Immune restoration following hematopoietic stem cell transplantation: an evolving target. Auletta JJ, Lazarus HM. Bone Marrow Transplant. 2005;35: 835-57.

The goals of the authors of this review were to (1) review immune effector cells and their function as they relate to HSCT, (2) review immune reconstitution across transplant regimens and stem cell sources; and (3) offer potential considerations for modulating or restoring immune responses during HSCT. They provide a detailed review (22 pages) including 5 tables and a figure.

In regard to stem cell source used during HSCT, the authors indicate that rates of life-threatening opportunistic infection were similar between pediatric UCB and age-/GVHD-matched sibling-donor BM recipients. UCB patients had higher naïve /CD4+ T cells, TREC levels, and TCR diversity after 2 years post-transplant despite receiving lower CD34+ cells. In contrast, when compared to HLA-matched unrelated donor allogeneic transplantation in adults, UCB recipients had higher infection rates during the first 50 days post-transplant and greater overall bacterial infections attributed to delayed PMN cell and lymphocyte recovery.

This paper reviews current understanding for immune restoration following HSCT and the novel ways in which to restore immune function and decrease transplant-related toxicity in the transplant recipient. The authors provide a detailed discussion of immunotherapy, including cellular factors as targets for immunotherapy, expansion of beneficial cell types, depletion of harmful effector cells, soluble factors and their targets, hematopoiesis and stem cell mobilization, activation or augmentation of effector cell function, inactivation or attenuation of effector cell function, effector cell localization and migration, tissue protection and restoration and immunomodulation, as well as a discussion of future directions.

14. Immune reconstitution following haematopoietic stem cell transplantation. Peggs KS, Mackinnon S. Br J Haematol. 2004;124:407-20.

The authors provide a comprehensive review of immune reconstitution following hematopoietic stem cell transplantation. The emphasis is on the extensive and complex laboratory evaluations that are available to research laboratories rather than on clinical data. The current state-of-the-art techniques for monitoring immune reconstitution are reviewed in depth. Details are provided regarding T-cell reconstitution including thymic-independent expansions and thymic-dependent reconstitution. Further information is provided regarding the influence of GVHD and chimerism status, reconstitution of antigen-specific T cell responses, B-cell reconstitution, NK cell reconstitution and the effect of stem cell source. The authors conclude that the tools are now available to more carefully dissect the interrelated elements of immune reconstitution, and to monitor the impact of attempts to enhance immune recovery. Although cytokine-based therapies and unselected DLI offer some potential, they point out that part of the immune defect posttransplantation is intentionally induced and maintained in order to limit the risk of development of GVHD. Increased knowledge about immune reconstitution may help to harness the immunological potential of allogeneic transplantation by guiding the need for, and appropriate timing of, post-transplantation interventions.

15. Long-term immune recovery of patients undergoing allogeneic stem cell transplantation: a comparison with their respective sibling donors. Sanchez-Guijo FM, Sanchez-Abarca LI, Bueno C, Villaron E, Lopez-Holgado N, Vazquez L, Lopez-Fidalgo J, Perez-Simon JA, Caballero MD, del Canizo MC, Orfao A, San Miguel JF. Biol Blood Marrow Transplant. 2005;11:354-61.

The major goal of this study was to evaluate the status of the immune system at least 1 year after transplantation in a series of 38 patients who had received an HLA-identical sibling allo-SCT and to compare it with that of their respective related donors. The study focused on the numeric and functional analysis not only of the different subsets of peripheral blood (PB) lymphocytes, but also of circulating dendritic cell (DC) subpopulations. The results were evaluated simultaneously in a patient/donor paired study performed only after complete bone marrow chimerism and normal PB cell counts were shown in all recipients. An additional goal of this study was to analyze the status of the immune system in a group of patients receiving a reduced-intensity conditioning (RIC) regimen as compared with those undergoing conventional myeloablative transplantations.

Results indicated the existence of several numeric and functional differences in distinct cellular compartments of the immune system of patients as compared with their respective donors. The most relevant numeric differences were related to the distribution of the distinct subsets of PB DCs (CD16⁺ DCs were increased, whereas myeloid and plasmacytoid DC subsets were decreased in the patient group). This was associated with an increased number of B cells, an inverted CD4/CD8 T-cell ratio, and a decrease in CD4⁺/CD8⁺ double-positive T cells in the patient group. In addition, a predominance of a T-helper 1 pattern of cytokine production (interferon γ and tumor necrosis factor α) with decreased secretion of T-helper 2-associated cytokines (interleukin 5 and interleukin 10) was also observed at the single-cell level. No significant differences were found in any of the parameters analyzed between patients receiving reduced-intensity conditioning regimens and those undergoing myeloablative transplantations.

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