ABSTRACT
We evaluated immune reconstitution in 58 adults who received hematopoietic SCTs from allogeneic siblings (allosib), matched unrelated donors (MUD) or cord blood (CB) at 90-day intervals for 1 year post transplant. CB recipients had a higher incidence of infections in the first 100 days compared with allosib and MUD recipients. The number of circulating T cells was lower in CB recipients compared with MUD recipients at 90 days and compared with allosib recipients at 180 days. Spectratype analysis of the TCR Vß complementarity determining region 3 (CDR3) of patient lymphocytes revealed that the TCR repertoire remained poorly diversified even at 360 days in nearly all patients. In contrast, the number of circulating B cells was significantly elevated in CB recipients compared with allosib recipients throughout the first year post transplant and compared with MUD recipients at 9-12 months. Spectratype analysis of the B-cell receptor V(H) CDR3 showed that the B-cell repertoire was diversified in most patients by 90 days. CD5(pos) B cells from assayed CB recipients expressed intracellular IL-10 early post transplant. Our data suggest that B cells, in addition to T cells, may have a role in impaired immune responses in CB transplant patients.
Subject(s)
B-Lymphocytes/immunology , Cord Blood Stem Cell Transplantation/adverse effects , Graft vs Host Disease/immunology , Immunocompromised Host , Opportunistic Infections/immunology , Adult , Aged , B-Lymphocytes/metabolism , CD5 Antigens/blood , CD5 Antigens/genetics , CD5 Antigens/metabolism , Complementarity Determining Regions/blood , Complementarity Determining Regions/chemistry , Complementarity Determining Regions/genetics , Complementarity Determining Regions/metabolism , Female , Graft vs Host Disease/blood , Graft vs Host Disease/epidemiology , Graft vs Host Disease/metabolism , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Illinois/epidemiology , Incidence , Interleukin-10/metabolism , Male , Middle Aged , Opportunistic Infections/blood , Opportunistic Infections/epidemiology , Opportunistic Infections/metabolism , Receptors, Antigen, B-Cell/blood , Receptors, Antigen, B-Cell/chemistry , Receptors, Antigen, B-Cell/genetics , Receptors, Antigen, B-Cell/metabolism , Receptors, Antigen, T-Cell/blood , Receptors, Antigen, T-Cell/chemistry , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Siblings , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Transplantation, HomologousABSTRACT
Costimulatory signals regulate T-cell activation. To investigate the role of costimulation in autoimmunity and transplantation, we studied the BB rat model of type 1 diabetes. Diabetes-prone BB (BBDP) rats spontaneously develop disease when 55-120 days of age. We observed that two anti-CD28 monoclonal antibodies (mAb) with different functional activities completely prevented diabetes in BBDP rats. Anti-CD154 mAb delayed diabetes, whereas treatment with CTLA4-Ig or anti-CD80 mAb accelerated disease. Anti-CD86 or anti-CD134L mAbs had no effect. Diabetes resistant BB (BBDR) rats are disease-free, but >95% of them develop diabetes after treatment with polyinosinic-polycytidylic acid and an mAb that depletes Treg cells. In the induced BBDR model, anti-CD154 mAb delayed onset of diabetes, whereas CTLA4-Ig, anti-CD134L or either of the anti-CD28 mAbs had little or no effect. In contrast, blockade of the CD134-CD134L pathway was highly effective for preventing autoimmune recurrence against syngeneic islet grafts in diabetic BBDR hosts. Blockade of the CD40-CD154 pathway was also effective, but less so. These data suggest that the effectiveness of costimulation blockade in the treatment of type 1 diabetes is dependent on both the costimulatory pathway targeted and the mechanism of induction, stage, intensity and duration of the pathogenic process.
