Mechanism of Accommodation in a Sensitized Human Leukocyte Antigen Transgenic Murine Cardiac Transplant Model.
Transplantation. 2012 Jan 23;
Authors: Fukami N, Ramachandran S, Narayanan K, Liu W, Nath DS, Jendrisak M, Chapman W, Mohanakumar T
Abstract
BACKGROUND: Presence of donor-specific antibodies (Abs) is detrimental to posttransplant allograft function. Some sensitized recipients have successfully undergone transplantation after pretransplant conditioning regimen using plasmapheresis and/or intravenous immunoglobulin therapy, but underlying mechanisms that confer such allograft protection are undefined. METHODS: We developed a single human leukocyte antigen (HLA)-mismatched heterotopic murine heart transplant model (HLA-A2 into HLA-A2-sensitized-C57BL/6) to determine whether pretreatment of donors with low concentration of HLA class I (W6/32) or control Ab (C1.18.4) will confer protection. Expression levels of survival genes, Bcl-2 and heme oxygenase-1, were analyzed by gene array analysis and quantitative real-time polymerase chain reaction. Expression levels of cytokine panel were analyzed by Luminex. Role of Bcl-2 in the induction of allograft protection was analyzed by silencing the Bcl-2 expression in the donor hearts using a small hairpin (shRNA) specific for Bcl-2. RESULTS: Control Ab-pretreated hearts were rejected in less than 5 days demonstrating hemorrhage, Ab, and C4 deposition. In contrast, W6/32-pretreated hearts were rejected at 15 days (P<0.05) that was prolonged to 25 days with antilymphocyte serum treatment. W6/32-pretreated hearts on day 5 exhibited increased expression of Bcl-2 (5.5-folds), Bcl-xl (5.5-folds), and heme oxygenase-1 (4.4-folds); decreased expression of ICAM-1, VCAM-1 (3.2-fold), along with reduced levels of cytokines interleukin (IL)-1β (4.4-folds), tumor necrosis factor α (3.7-folds), IL-6 (7.5-folds), IL-12 (2.3-folds) and chemokines monocyte chemotactic protein 1 (4.5-folds), MIG (4.4-folds), MIP-1α (3.4-folds), and IL-8 (3.1-folds). Silencing of Bcl-2 in accommodated hearts before transplant resulted in loss of protection with rejection (9±3 vs. 15±2days, P<0.05). CONCLUSION: Pretreatment of hearts with low levels of anti-HLA Abs increases expression of antiapoptotic genes that inhibits caspases, leading to decreased inflammatory cytokines and chemokines, which promote allograft survival.
PMID: 22273841 [PubMed - as supplied by publisher]
Dendritic Cells With TGF-β1 and IL-2 Differentiate Naive CD4+ T Cells Into Alloantigen-Specific and Allograft Protective Foxp3+ Regulatory T Cells.
Transplantation. 2012 Jan 20;
Authors: Yang H, Cheng EY, Sharma VK, Lagman M, Chang C, Song P, Ding R, Muthukumar T, Suthanthiran M
Abstract
BACKGROUND: Naturally occurring, thymic-derived Foxp3+CD25+CD4+ regulatory T cells (nTregs) are pivotal for the maintenance of self-tolerance. nTregs, however, are sparse and lack alloantigen specificity, and these properties pose challenges for their use in clinical transplantation. METHODS: We established mixed leukocyte reaction (MLR) with dendritic cells (DCs) as stimulators and CD4+ T cells as responders and supplemented the MLR with IL-2 and TGF-β1 and investigated whether DCs+IL-2+TGF-β1 differentiate the polyclonal CD4+ cells into alloantigen-specific and allograft protective Tregs. RESULTS: We found a greater than a 10-fold increase in Foxp3+CD25+ subpopulation (P<0.01) following stimulation of BALB/c CD4+ cells with C57BL/6 (B6) CD11c+ DCs+IL-2+TGF-β1 in the MLR. Levels of TGF-β1 messenger RNA (mRNA) (P=0.01) and the ratios of TGF-β1 mRNA to granzyme B mRNA (P=0.0003) and Foxp3 mRNA to granzyme B mRNA (P<0.01) were higher in alloantigen-induced Tregs (alloTregs) compared with nTregs. alloTregs suppressed MLR at a 16:1 responder to suppressor ratio, whereas nTregs suppressed at 4:1. Suppression by alloTregs was alloantigen specific and was observed at the level of responder cells and at the level of stimulator cells. In a fully H-2-mismatched, nonlymphopenic, immunocompetent mouse islet transplantation model, alloTregs but not nTregs prolonged survival of islet allografts without any other immunosuppressive therapy (P=0.0003), and the protection was alloantigen specific. CONCLUSIONS: A combination of CD11c+ DCs, IL-2, and TGF-β1 may help differentiate naive, high abundant CD4+ T into alloantigen-specific and allograft protective Foxp3+Tregs.
PMID: 22270834 [PubMed - as supplied by publisher]
Antibodies Directed Against AB Blood Antigens or Human Leukocyte Antigen Molecules Activate Different Intracellular Pathways Explaining Their Differential Effects Toward Accommodation.
Transplantation. 2012 Jan 24;
Authors: Le Bas-Bernardet S, Blancho G
PMID: 22277981 [PubMed - as supplied by publisher]
Impact of Donor and Recipient Race on Survival After Hepatitis C-Related Liver Transplantation.
Transplantation. 2012 Jan 24;
Authors: Layden JE, Cotler SJ, Grim SA, Fischer MJ, Lucey MR, Clark NM
Abstract
BACKGROUND: Both donor and recipient race impact outcomes after liver transplantation (LT), especially for hepatitis C virus (HCV). The interaction and simultaneous impact of both on patient survival is not clearly defined. The purpose of this study was to examine the impact of donor and recipient race on recipient and graft survival after HCV-related LT using the United Network for Organ Sharing database. METHODS: A total of 16,053 recipients (75.5% white, 9.3% black, and 15.2% Hispanic) who underwent primary LT for HCV between 1998 and 2008 were included. Cox regression models were used to assess the association between recipient/donor race and patient survival. RESULTS: A significant interaction between donor and recipient race was noted (P=0.01). Black recipients with white donors had a higher risk of patient mortality (adjusted hazard ratio, 1.66; 95% confidence interval, 1.47-1.87) compared with that of white recipients with white donors. In contrast, the pairing of Hispanic recipients with black donors was associated with a lower risk of recipient mortality compared with that of white recipients with white donors (adjusted hazard ratio, 0.64; 95% confidence interval, 0.46-0.87). Similar results were noted for graft failure. CONCLUSION: In conclusion, the impact of donor and recipient race on patient survival varies substantially by the matching of recipient/donor race.
PMID: 22277982 [PubMed - as supplied by publisher]
BACKGROUND: ABO incompatible (ABOi) kidney transplantation is an important modality to facilitate living donor transplant for incompatible pairs. To date, reports of the outcomes from this practice in the United States have been limited to single-center studies. METHODS: Using the Scientific Registry of Transplant Recipients, we identified 738 patients who underwent live-donor ABOi kidney transplantation between January 1, 1995, and March 31, 2010. These were compared with matched controls that underwent ABO compatible live-donor kidney transplantation. Subgroup analyses among ABOi recipients were performed according to donor blood type, recipient blood type, and transplant center ABOi volume. RESULTS: When compared with ABO compatible-matched controls, long-term patient survival of ABOi recipients was not significantly different between the cohorts (P=0.2). However, graft loss was significantly higher, particularly in the first 14 days posttransplant (subhazard ratio, 2.34; 95% confidence interval, 1.43-3.84; P=0.001), with little to no difference beyond day 14 (subhazard ratio, 1.28; 95% confidence interval, 0.99-1.54; P=0.058). In subgroup analyses among ABOi recipients, no differences in survival were seen by donor blood type, recipient blood type, or transplant center ABOi volume. CONCLUSIONS: These results support the use and dissemination of ABOi transplantation when a compatible live donor is not available, but caution that the highest period of risk is immediately posttransplant.
PMID: 22290268 [PubMed - as supplied by publisher]
A Randomized Controlled Trial of Intravenous or Oral Iron for Posttransplant Anemia in Kidney Transplantation.
Transplantation. 2012 Jan 27;
Authors: Mudge DW, Tan KS, Miles R, Johnson DW, Badve SV, Campbell SB, Isbel NM, van Eps CL, Hawley CM
Abstract
BACKGROUND: Anemia after kidney transplantation has been associated with poor transplant outcomes. We hypothesized that intravenous (IV) iron may more rapidly correct anemia than oral (PO) iron. METHODS: One hundred four kidney transplant recipients were prospectively randomized to IV iron polymaltose (500 mg single dose) or PO ferrous sulfate (210 mg elemental iron daily, continuously). The primary outcome was time to resolution of anemia, defined as hemoglobin more than or equal to 11 g/dL. Secondary outcomes included infections, blood transfusions, gastrointestinal side-effects, and acute rejection. RESULTS: There was no significant difference in the primary outcome comparing IV with PO iron (hazards ratio 1.22; 95% confidence interval 0.82-1.83; P=0.32). The median time to resolution of anemia was 12 days in the IV group versus 21 days in the PO group. There were no differences in infections (20% vs. 24%, P=0.62), acute rejection (8% vs. 6%, P=0.68), blood transfusions (10% vs. 18%, P=0.24), and severe gastrointestinal side-effects (6% vs. 12%, P=0.29) between the IV iron and the PO iron groups. CONCLUSIONS: We conclude that a single dose of IV iron did not result in more rapid resolution of anemia compared with PO iron. Both IV and PO iron are safe and effective in the management of posttransplant anemia.
PMID: 22290270 [PubMed - as supplied by publisher]
PubMed requires this notice of disclaimer is present.
