ABSTRACT
Regulatory T cells (Tregs) modulate immune responses and improve survival in murine transplant models. However, whether the Treg content of allogeneic cell grafts influences the outcome in human haematopoietic stem cell (HSC) transplantation is not well established. In a prospective study of 94 adult allogeneic PBSC transplants (60% unrelated; 85% reduced intensity conditioning), the median Treg (CD3(+)CD4(+)CD25(+)FOXP3(+)CD127(dim/-)) dose transplanted was 4.7 × 10(6)/kg, with Tregs accounting for a median of 2.96% of CD4(+) T cells. Patients transplanted with grafts containing a Treg/CD4(+) T-cell ratio above the median had a 3-year overall survival of 75%, compared with 49% in those receiving grafts with a Treg/CD4(+) T-cell ratio below the median (P=0.02), with a 3-year non-relapse mortality of 13% and 35%, respectively (P=0.02). In multivariate analysis, a high graft Treg/CD4(+) T-cell ratio was an independent predictor of lower non-relapse mortality (hazard ratio (HR), 0.30; P=0.02), improved overall survival (HR, 0.45; P=0.03) and improved sustained neutrophil (HR, 0.52; P=0.002), platelet (HR, 0.51; P<0.001) and lymphocyte (HR, 0.54; P=0.009) recovery. These data support the hypothesis that the proportion of Tregs in allogeneic HSC grafts influences clinical outcome and suggest that Treg therapies could improve allogeneic HSC transplantation.
Subject(s)
Graft Survival , Hematologic Neoplasms , Hematopoietic Stem Cell Transplantation , T-Lymphocytes, Regulatory , Adolescent , Adult , Aged , Allografts , Animals , Disease-Free Survival , Female , Hematologic Neoplasms/blood , Hematologic Neoplasms/mortality , Hematologic Neoplasms/therapy , Humans , Lymphocyte Count , Male , Mice , Middle Aged , Survival RateABSTRACT
The impact of ABO incompatibility on clinical outcomes following haematopoietic SCT (HSCT) remains controversial. This retrospective study assessed the effect of ABO mismatch on transplant outcomes and transfusion requirements in 594 patients undergoing reduced-intensity conditioned (RIC) HSCT with alemtuzumab in three UK transplant centres. We found no significant effects of minor, major or bidirectional ABO mismatch on overall survival, relapse-free survival, nonrelapse mortality or relapse incidence. Although the rate of acute GVHD was unaffected by ABO mismatch, the incidence of extensive chronic GVHD was higher in patients with minor and major mismatch compared with those who were ABO matched (hazard ratio (HR) 1.74, P=0.032 for minor, HR 1.69 P=0.0036 for major mismatch). Red cell and platelet transfusion requirements in the first 100 days post transplant did not differ by ABO mismatch. In this large UK series, ABO mismatch in RIC HSCT has no clinically significant effect on survival outcomes but appears to modify susceptibility to extensive chronic GVHD.
Subject(s)
ABO Blood-Group System/immunology , ABO Blood-Group System/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Transplantation, Homologous/methods , Adolescent , Adult , Aged , Alemtuzumab , Antibodies, Monoclonal, Humanized , Female , Humans , Male , Middle Aged , Treatment Outcome , Young AdultSubject(s)
Bronchiolitis Obliterans , Databases, Factual , Graft vs Host Disease , Stem Cell Transplantation , Adolescent , Adult , Aged , Allografts , Bronchiolitis Obliterans/epidemiology , Bronchiolitis Obliterans/etiology , Bronchiolitis Obliterans/physiopathology , Graft vs Host Disease/epidemiology , Graft vs Host Disease/etiology , Graft vs Host Disease/physiopathology , Hematologic Neoplasms/epidemiology , Hematologic Neoplasms/physiopathology , Hematologic Neoplasms/therapy , Humans , Male , Middle Aged , Respiratory Function Tests , Retrospective StudiesABSTRACT
Myeloablative allo-SCT decreases relapse incidence (RI) in ALL. Reduced intensity conditioning (RIC) may extend allo-SCT to older and less fit patients. Sixty-nine ALL patients reported to the BSBMT underwent fludarabine-based RIC allo-SCT, 38 from unrelated donors (UD). Forty-four patients received alemtuzumab. ALL was in CR in 64 patients (93%). This was a second or third SCT in 23 patients. Two-year OS and PFS were 36% and 32%, respectively. In multivariate analysis male recipients demonstrated better OS and PFS (hazard ratio (HR) = 0.42, P = 0.008 and HR = 0.45, P = 0.012, respectively). Two-year TRM was 29%: higher with younger age (HR = 0.97/year, P = 0.041), female recipient (HR = 2.55, P = 0.049) and increasing grade of acute GVHD (HR = 1.87, P = 0.001). Two-year RI was 38% and was lower in patients with acute and chronic GVHD (HR = 0.62 per increasing grade, P = 0.035 and HR = 0.52, P = 0.025, respectively). Long-term ALL-free survival is achievable following fludarabine-based RIC allo-SCT. The association between GVHD and decreased RI suggests the presence of a GVL effect.
Subject(s)
Graft vs Leukemia Effect , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Stem Cell Transplantation , Transplantation Conditioning , Acute Disease , Adolescent , Adult , Age Factors , Alemtuzumab , Allografts , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents/administration & dosage , Disease-Free Survival , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Graft vs Host Disease/therapy , Humans , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Sex Factors , Societies, Medical , Survival Rate , United Kingdom , Vidarabine/administration & dosage , Vidarabine/analogs & derivativesABSTRACT
Cryopreservation of PBSC for allo-SCT offers potential advantages; however, its impact on engraftment and outcomes remains unclear. A total of 76 allo-SCT performed using cryopreserved PBSC from HLA identical related (n=57) and unrelated donors (n=19) were compared with 123 fresh PBSC allo-SCT. Median neutrophil engraftment was on day 12 for both cryopreserved and fresh PBSC; in multivariate analysis, there was a slight but significant delay in neutrophil engraftment after the median date (hazard ratio (HR)=1.44, P=0.003). Platelet engraftment was significantly delayed in cryopreserved PBSC recipients (median time 19 vs 14 days). In multivariate analysis cryopreservation (HR=1.85, P<0.001), earlier date of transplant and lower CD34+ cell dose were associated with delayed platelet engraftment. Two-year OS and relapse and 1-year TRM rates did not differ significantly. Acute GVHD incidence was comparable, and extensive chronic GVHD at 1 year was higher in cryopreserved PBSC recipients (40.3 vs. 28.3%), but not significantly so (P=0.13). Cryopreservation of related and unrelated donor allogeneic PBSC is safe and effective where its benefits outweigh the risks of delayed platelet engraftment; its impact on chronic GVHD incidence requires further assessment.
Subject(s)
Blood Platelets/cytology , Cryopreservation/methods , Neutrophils/cytology , Adult , Aged , Female , Humans , Male , Middle Aged , Peripheral Blood Stem Cell Transplantation , Recurrence , Survival Analysis , Tissue Donors , Transplantation, Homologous , Unrelated Donors , Young AdultABSTRACT
Extracorporeal photopheresis (ECP) has become a recognised treatment for steroid-refractory chronic GVHD (cGVHD), but the optimal frequency and duration of treatment are yet to be established. We report on 82 consecutive patients with mucocutaneous cGVHD who received a bimonthly regimen of ECP treatment for two consecutive days, which could be subsequently tapered to a monthly regimen depending on response. Patients were steroid-refractory, steroid-dependent or steroid-intolerant, and 29 (35%) had multiorgan involvement. The median duration of treatment was 330 days (42-987). The median number of ECP cycles was 15 (1.5-32). Response was assessed by clinical assessment and reduction in immunosuppression after 6 months. 69/82 (84%) had completed 6 months of ECP and 65/69 (94%) had ≥ 50% improvement in symptoms and signs of cGVHD. A total of 77% of patients who completed 6 months of ECP had a reduction in immunosuppression dose and 80% had decreased their steroid dose (27.5% stopped, 30% had ≥ 75% reduction, 17.5% had ≥ 50% reduction and 25% had <50% reduction). OS at 3 years from the start of ECP was 69%. This study reports the largest series of patients receiving bimonthly ECP treatment for cGVHD, and confirms that ECP allows successful reduction of immunosuppression.
Subject(s)
Graft vs Host Disease/therapy , Photopheresis/methods , Skin Diseases/therapy , Adolescent , Adult , Aged , Chronic Disease , Female , Hematologic Neoplasms/therapy , Humans , Male , Middle Aged , Time FactorsABSTRACT
Paraproteinaemia following allo-SCT is common. We analysed 91 consecutive patients undergoing allo-SCT; conditioning included alemtuzumab in 42% of the patients. Paraproteinaemia incidence at 2 years was 32%. In univariate analysis paraproteinaemia was associated with unrelated donor, age, recipient seropositivity for CMV and alemtuzumab conditioning (hazard ratio (HR) 3.93, P=0.0006). Paraproteinaemia was not associated with haematological diagnosis; disease status at transplant; varicella zoster, herpes simplex or EBV serology; reduced-intensity vs myeloablative conditioning or GVHD. CMV reactivation-more frequent in alemtuzumab recipients-was associated with paraproteinaemia (HR 7.52, P<0.0001). In multivariate analysis, only increasing age (HR 1.04 per year, P=0.048) and CMV reactivation (HR 5.74, P=0.001) were significantly associated with paraproteinaemia. Alemtuzumab without CMV reactivation, however, resulted in significantly more paraproteinaemia, suggesting an effect that is independent of CMV reactivation. OS was poorer in patients with paraproteinaemia (HR 2.54, P=0.04) and relapse increased (HR 2.38, P=0.087). Paraproteinaemia was not significantly independently associated with decreased survival on multivariate analysis. Post transplant paraproteinaemia is associated with CMV reactivation, is more frequent in alemtuzumab-conditioned transplants and is not associated with improved OS.
Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Neoplasm/adverse effects , Cytomegalovirus/physiology , Hematopoietic Stem Cell Transplantation/adverse effects , Paraproteinemias/etiology , Transplantation Conditioning/adverse effects , Adult , Alemtuzumab , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Neoplasm/administration & dosage , Cytomegalovirus/immunology , Female , Humans , Male , Middle Aged , Paraproteinemias/chemically induced , Paraproteinemias/immunology , Paraproteinemias/virology , Retrospective Studies , Survival Analysis , Virus ActivationABSTRACT
Proteolysis is required for two steps of the MHC class II antigen-processing pathway, degradation of invariant chain and cleavage of protein antigens. Invariant chain dissociation from MHC is limited by a final proteolytic event which is tightly regulated in both temporal and tissue-specific ways. In contrast, enzymes involved in antigen proteolysis remain ill-defined. Gene 'knockout' experiments of housekeeping proteolytic enzymes suggest either that these enzymes do not play a major role, or that antigen proteolysis is too degenerate for this type of analysis. The possible role of two other proteinases, cathepsin E and aspariginyl endopeptidase is discussed. Finally, the data implicating antigen processing in repertoire generation is briefly considered. We conclude that selective regulation of endosomal proteolysis could have profound implications for control of immunity against infection, as well as in autoimmunity.
Subject(s)
Antigen Presentation , Antigens/metabolism , Endopeptidases/metabolism , Histocompatibility Antigens Class II/metabolism , Peptide Fragments/metabolism , Amino Acid Sequence , Animals , Antigen-Presenting Cells/immunology , Antigens, Differentiation, B-Lymphocyte/metabolism , CD4-Positive T-Lymphocytes/immunology , Endocytosis , Histocompatibility Antigens Class II/immunology , Humans , Molecular Chaperones/metabolism , Molecular Sequence DataABSTRACT
IFN-gamma is a crucial mediator in the induction of cell-mediated Th1-type responses but is predominantly a negative regulator of B cell differentiation and proliferation. This cytokine is therefore a key factor in determining Th1 vs Th2 differentiation. This study investigates the action of IFN-gamma in modulation of HLA-DR expression and Ag presentation by EBV-transformed human B cell lines. In contrast to its action on the monocyte/macrophage, IFN-gamma down-regulates surface MHC expression on these B cells, and this regulation is posttranscriptional. In parallel with MHC down-regulation, there is a reduced capability to process and present exogenous protein and peptide Ag to T cell hybridomas. IFN-gamma does not change the rates of fluid phase endocytosis or exocytosis in this model system but correlates with an up-regulation of the lysosomal enzymes cathepsins B and D.
Subject(s)
Antigen Presentation/immunology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Down-Regulation/immunology , Histocompatibility Antigens Class II/biosynthesis , Interferon-gamma/pharmacology , Animals , Antigen Presentation/genetics , Apoptosis/immunology , B-Lymphocytes/enzymology , Cathepsins/antagonists & inhibitors , Cathepsins/biosynthesis , Cathepsins/metabolism , Cell Line, Transformed , Cell Membrane/immunology , Cell Membrane/metabolism , Endocytosis/immunology , HLA-D Antigens/metabolism , Histocompatibility Antigens Class II/genetics , Humans , Hybridomas/immunology , Hybridomas/metabolism , Mice , Muramidase/immunology , Muramidase/metabolism , Transfection/immunologyABSTRACT
T cells recognizing poorly displayed self determinants escape tolerance mechanisms and persist in the adult repertoire. The process by which these T cells are primed is not clear, but once activated, they can cause autoimmunity. Here, we show that dendritic cells treated with interleukin 6 (IL-6) process and present determinants from a model native antigen in a qualitatively altered hierarchy, activating T cells in vitro and in vivo against determinants that were previously cryptic because of poor display. IL-6 does not induce conventional maturation of dendritic cells but alters the pH of peripheral, early endosomal compartments and renders the cells more susceptible to killing by chloroquine. Acidification of endosomes by ouabain mimics the effect of IL-6 and allows processing of the same cryptic determinant. These results suggest that cytokines such as IL-6 could initiate and help to propagate an autoimmune disease process by differentiating dendritic cells into a state distinct from that induced by normal maturation.