Altered homeostasis of CD4(+) memory T cells in allogeneic hematopoietic stem cell transplant recipients: chronic graft-versus-host disease enhances T cell differentiation and exhausts central memory T cell pool.

Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Biology of Blood and Marrow Transplantation (Impact Factor: 3.35). 11/2007; 13(10):1176-84. DOI: 10.1016/j.bbmt.2007.06.009
Source: PubMed

ABSTRACT An increased risk of late infection is a serious complication after allogeneic hematopoietic stem cell transplantation (AHSCT), especially for recipients with defective CD4(+) T cell recovery. Although chronic graft-versus-host disease (cGVHD) negatively influences CD4(+) T cell reconstitution, the mechanisms leading to this defect are not well understood. We found that the proportion of CD27(-) CD4(+) T cells was remarkably increased in ASHCT recipients with cGVHD or with repetitive infectious episodes. Isolated CD27(-) CD4(+) T cells from ASHCT recipients had significantly shortened telomere length, displayed enhanced vulnerability to activation-induced cell death, and showed extremely reduced clonal diversity, when compared with CD27(-) CD4(+) T cells from healthy donors. Also, CD27(+) CD4(+) T cells from AHSCT recipients easily lost their expression of CD27 in response to antigen stimulation regardless of cGVHD status. Taken together, these data indicate that homeostasis of memory CD4(+) T cells from AHSCT recipients is altered, and that they easily transit into CD27(-) effector memory T cells. Increased in vivo T cell stimulation observed in recipients with cGVHD further promotes the transition to effector memory cells, a change that decreases the central memory CD4(+) T cell pool and consequently weakens the recipient's defense against persistently infecting pathogens.

  • [Show abstract] [Hide abstract]
    ABSTRACT: CD4 T cells play a significant role in the pathogenesis of rejection, providing help to alloreactive CD8 and B cells, however, the exact contribution of each memory compartment in vivo has not been defined. They are also important for the maintenance of tolerance due to regulatory activity of specialized subsets. In this study, we assessed changes in frequencies of functionally distinct lymphocyte subsets of peripheral blood (PBLs) in 26 heart transplant recipients (HT) in association with rejection episodes. Patients who developed rejection (n = 7), namely Grade 3B (n = 1), 3A (n = 4), or 2 (n = 2), in comparison with those with stable graft function displayed at baseline (pre-HT) higher percentages of naive (CCR7+CD45RA+) CD4 T cells (median 48 vs 36.6%; P = .035) and lower percentages of central memory (CCR7+CD45RA-) CD4 T cells (33.3 vs 46.5%; P = .035). At 30 days post-HT, CD4/CD127(low)FoxP3+ T cells were significantly reduced among patients with rejection episodes (0.84 vs 2.15%; P = .042). CD8 final effector T cells were increased at 90 days post-HT among those patients who experienced rejection (TEM2: 60.8 vs 31.9%; P < .1), at the expense of shrinking CD8 central memory compartment (TCM: 8.6 vs 12.9%; P = .046). The potential role of T-cell memory distribution should be further evaluated in HT patients as possible markers to discriminate patients at risk for rejection.
    Transplantation Proceedings 07/2009; 41(6):2480-4. · 0.95 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mononuclear phenylglyoxylato- and 4-R-benzoatocopper(II) complexes with two different 1,3-bis(2-arylimino)isoindoline ligands (aryl = pyridyl, or benzimidazolyl) have been synthesized and characterized. Coordination mode of the carboxylate ligands is very similar (monodentate) in each case, while redox behavior of the copper center is dependent on the aryl- and 4-R-substituents. The supramolecular assembly in the solid state via hydrogen bonds and π-stacking between the ligands can be influenced by the aryl-group and carboxylate ligand.
    Inorganic Chemistry Communications 11/2011; 14:1767-1772. · 2.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Defective immune reconstitution is a major barrier to successful hematopoietic cell transplantation (HCT), and has important implications in the pediatric population. There are many factors that affect immune recovery, including stem cell source and graft-versus-host disease (GVHD). Complete assessment of immune recovery, including T and B lymphocyte evaluation, innate immunity, and response to neoantigens, may provide insight as to infection risk and optimal time for immunizations. The increasing use of cord blood grafts requires additional study regarding early reconstitution and impact upon survival. Immunization schedules may require modification based upon stem cell source and immune reconstitution, and this is of particular importance as many children have been incompletely immunized, or not at all, before school entry. Additional studies are needed in children post-HCT to evaluate the impact of differing stem cell sources upon immune reconstitution, infectious risks, and immunization responses.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2011; 18(1):6-15. · 3.15 Impact Factor