Serum Neopterin Levels Among Hepatitis C-Positive Living-Donor Renal Transplant Recipients.

BACKGROUND: The role of neopterin as a marker of cell-mediated immunity for immunological monitoring after transplantation is of great potential interest. Neopterin levels among hepatitis C virus (HCV)-positive recipients of living-donor renal transplantation (LDRT) have not been previously described. METHODS: Twenty-two HCV-positive (group I) and 10 HCV-negative (group II) recipients of LDRT were serially monitored for serum neopterin levels by enzyme-linked immunosorbent assay (ELISA). Group I patients were monitored thrice, ie, before transplantation, day 10, and 6 months post transplantation, while group II patients were monitored twice (day 10 and 6 months post transplantation). Peripheral blood T-lymphocyte subsets (CD3, CD4, CD8, CD4(+)CD25(+), CD16+56) and Th1/Th2 cytokines were monitored concomitantly by flow cytometry. RESULTS: Ten days post transplantation, there was a significant increase in neopterin and neopterin/creatnine levels among group I patients. There was a positive correlation between activated T-lymphocyte (CD4(+)CD25(+)) and neopterin early post transplantation (day 10). Th2 cytokines IL-10 and IL-5 showed a positive correlation with neopterin levels on day 10 and 6 months post transplantation, respectively. Neopterin levels did not show association with either HCV viral load or allograft rejection among our study cohort. CONCLUSION: Increased monocyte/macrophage activation with elevated serum neopterin was detected among group I patients on day 10 post transplantation, but it could not predict rejection. It appears that IL-10 either from a regulatory or nonregulatory source helps in the maintenance of stable graft early post transplantation. Further, it would be of interest to assess the role of neopterin in chronic allograft nephropathy and long-term graft outcome.

Endogenous IL-22 plays a dual role in arthritis: regulation of established arthritis via IFN-γ responses.

OBJECTIVE: IL-22 is elevated in patients with inflammatory arthritis and correlates with disease activity. IL-22 deficient mice have reduced incidence of arthritis. Recombinant IL-22 restrains progression of arthritis via increase in IL-10 responses when administered prior to onset of arthritis. These findings imply a possible dual role of IL-22 in inflammatory arthritis depending on the phase of arthritis. Experiments outlined here were designed to elucidate the contribution of endogenous IL-22 before and after the onset of arthritis. METHODS: Collagen induced arthritis (CIA) was induced in DBA1 or IFN-γ deficient mice following immunization with collagen and complete Freund's adjuvant. Anti-IL-22 antibody or isotype control were administered prior to or after onset of arthritis and disease progression assessed by clinical scoring and histopathology. IL-22, IL-17 and IFN-γ responses were measured by ELISA and flowcytometry. Anti-collagen antibody responses were analyzed by ELISA. Expression of IL-22R1 in CD4+ cells was elucidated by flowcytometry and real time PCR. RESULTS: Collagen specific IL-22 responses were expanded during arthritis and IL-22 producing cells were discrete from IL-17 or IFN-γ producing cells. Neutralization of IL-22 after onset of arthritis resulted in significant increase in Th1 responses and significantly reduced severity of arthritis. CD4+ cells from arthritic mice showed increased surface expression of IL-22R1. In vitro, CD4+T cells cultured with antigen presenting cells in the presence or absence of IL-22 suppressed or induced IFN-γ, respectively. The protective effect of anti-IL-22 was reversed in IFN-γ deficient mice. Moreover, administration of anti-IL-22 prior to onset of arthritis augmented arthritis severity. CONCLUSION: We show for the first time that IL-22 plays a dual role: protective prior to the onset of arthritis and pathogenic after onset of arthritis. The pathogenic effect of IL-22 is dependent on suppression of IFN-γ responses. IL-17 responses remained unchanged with the administration of anti-IL22 antibody. IL-22R1 is upregulated on CD4+T cells during arthritis and regulates IFN-γ in T cells.

Interleukin-22 reduces the severity of collagen-induced arthritis in association with increased levels of interleukin-10.

OBJECTIVE: The mechanism of action of interleukin- 22 (IL-22) in inflammatory arthritis remains unknown. IL-22-deficient mice exhibit an intact humoral and cellular immune response to collagen and yet have a reduced incidence of collagen-induced arthritis (CIA). Further, administration of anti-IL-22 does not reduce the severity of clinical arthritis but rather improves only certain aspects of joint inflammation as assessed histologically. This study was undertaken to investigate the mechanism of action and role of systemic IL-22 in modulating target organ inflammation. METHODS: CIA was induced in DBA mice by immunization with collagen and Freund's complete adjuvant. Expression of IL-22 and its receptor (IL-22R) in lymphoid organ and target tissues was determined during various phases of arthritis. The effector functions of IL-22 on induction/regulation of various cytokines in in vitro restimulation cultures were analyzed by enzyme-linked immunosorbent assay (ELISA). Recombinant IL-22 with or without anti-IL-10 antibody was administered to mice following immunization with collagen and prior to the onset of arthritis, and the severity of arthritis was evaluated by clinical scoring and histopathologic assessment. Anticollagen antibodies in mouse sera were analyzed by ELISA. RESULTS: IL-22 and IL-22R were up-regulated in lymphoid organs and joints during the course of arthritis. IL-22 augmented IL-10, IL-17, and IL-6 in lymphoid tissues in vitro. Administration of recombinant IL-22 was associated with an increase in IL-10 levels in vivo and a significant reduction in the progression of arthritis severity. Anti-IL-10 antibody treatment was associated with the abrogation of this protective effect of IL-22. CONCLUSION: Our data demonstrate, for the first time, that IL-22 has a protective role in inflammatory arthritis.

Cellular immune response and cytokine profile among hepatitis C positive living donor renal transplant recipients.

BACKGROUND: Hepatitis C virus (HCV) infection is prevalent among renal transplant recipients. METHODS: Twenty-five recipients of living donor renal transplantation with HCV (group I) and without HCV (group II) were serially monitored at three time points, that is, pretransplant, day 10, and 6 months posttransplant. Phenotypic characterization of T-cell subsets and natural killer cells was performed by flow cytometric immunophenotyping. Cytometric bead array immunoassay was used to simultaneously measure six cytokines (interleukin [IL]-2, IL-4, IL-5, IL-10, tumor necrosis factor-α, and interferon-γ) from phytohemagglutin-stimulated culture supernatants, and transforming growth factor (TGF)-ß1 levels were determined by ELISA. Real-time polymerase chain reaction method was used to determine the serum viral load among group I patients at three time points. RESULTS: Group I patients on day 10 posttransplant showed a significant increase in T cells subsets with reduced interferon-γ and increased TGF-ß1 levels. A significantly increased CD8 T cells and TGF-ß levels were seen at 6-month posttransplant among group I patients. Multivariate linear regression analysis showed TGF-ß and tumor necrosis factor-α as the most significant predictors affecting early (day 10) and late (6 months) posttransplant viral load, respectively. CONCLUSION: After an initial increase in the viral load immediately posttransplantation, there is a reduction in viral load. A concomitant timed dissection of the immune response shows a complex interactive environment in which, despite immunosuppression, not only the antiviral immune response persists but the virus is also able to modulate the host immune response for its survival. Per se, HCV does not adversely affect the allograft or patient outcome in this case-control study.