[show abstract][hide abstract] ABSTRACT: 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.
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.
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).
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.
[show abstract][hide abstract] ABSTRACT: Little information has been published about the suitability of candidates for living organ donation who have a past or current psychiatric diagnosis. A retrospective review of 445 living donor kidney transplants performed at Barnes-Jewish Hospital's transplant center from 1995 to 2005 disclosed 42 donor candidates with such a history, prompting detailed psychological evaluation. Although 41 candidates (10% of the donor pool) met criteria for 1 or more psychiatric diagnoses, none were considered psychologically unfit for donation. Of these, 22 candidates underwent kidney donation without medical or surgical complications and without development of subsequent active psychological problems. Several donors maintained long-term contact up to 12 years to report good health and a high degree of satisfaction with the decision to donate. This experience suggests that for donor candidates with a psychiatric diagnosis, formal psychiatric evaluation to evaluate current mental health stability is warranted. Stable individuals, on or off therapy, can be considered fit to donate with expected short- and long-term outcome prognoses similar to those for the general population.
[show abstract][hide abstract] ABSTRACT: In recent years, transplantation of islets and pancreas has become a viable option for patients debilitated with type I diabetes. The success of islet transplantation has been attributed to the ability to isolate high quality islets for transplantation and capacity to maintain the recipient's immunosuppressive levels within a specific target range following transplantation. The purpose of this study was to determine the role of pretransplant sensitization to human leukocyte antigen (HLA) in islet transplantation.
We retrospectively analyzed seven patients that were transplanted with islets under the auspices of the Juvenile Diabetes Research Foundation and Islet Cell Resource Center/National Institutes of Health. Humoral sensitization towards donor antigens both prior to and following islet transplantation was detected by FLOW panel reactive antibodies (PRA) and donor-specific cellular sensitization was detected by performing enzyme-linked immunospot assay analysis for cytokines interferon-gamma and interleukin-2.
Our analysis demonstrates that humoral and cellular sensitization to histocompatibility antigens prior to and after islet transplantation are associated with the failure of transplanted islets
Patient selection based on sensitization to donor HLA may be one of the factors crucial for the success of islet transplant. Further, in some patients, rejection of islets can be associated with sensitization to mismatched donor histocompatibility antigens.
[show abstract][hide abstract] ABSTRACT: Targeting 2-hr postdose cyclosporine (C2) levels to 1,000 to 1,700 mg/dL during the first 6 months after renal transplantation is recommended for triple immunosuppressive regimens. This trial determines whether lower C2 levels could be targeted safely in de novo kidney transplant recipients under a quadruple regimen compared with a similar cohort monitored with trough (C0) levels.
This single-center, sequential, cohort-designed trial included patients who received Thymoglobulin, corticosteroids, an antimetabolite, and cyclosporine monitored by C2 (n=50) or C0 (n=50). Cyclosporine was tapered to maintain the C2 between 1,000 and 1,200 ng/mL months 0 to 3 and between 600 and 1,000 ng/mL thereafter and C0 between 250 and 350 ng/mL months 0 to 3 and between 100 and 250 ng/mL thereafter.
Baseline patient and donor characteristics were similar. There were no differences in graft survival (100% C2 vs. 100% C0), acute rejection (4% C2 vs. 6% C0), allograft function, or adverse events at 6 months. C2 levels were lower than the suggested guidelines throughout the study (33% lower at 1 month and 48% lower at 6 months). Lower cyclosporine doses were achieved in the C2 arm compared with the C0 arm by 1 month and were sustained throughout the trial, which translated into an average cyclosporine cost savings of USD $773 in the C2 arm during the 6-month period (P<0.001).
With a quadruple immunosuppressive regimen and lower C2 targets than recommended for triple therapy, safe and effective cyclosporine minimization was achieved. Lower cyclosporine doses were achieved in C2-monitored patients compared with C0-monitored patients, translating into lower immunosuppressive costs.
[show abstract][hide abstract] ABSTRACT: Chronic lung allograft rejection in the form of bronchiolitis obliterans syndrome and its histopathologic correlate, obliterative bronchiolitis (OB), are a major source of morbidity and mortality after lung transplantation. Murine heterotopic tracheal transplants into fully allogeneic mismatched recipients develop obliterative airway disease (OAD), which is a suitable model of OB. Using this murine heterotopic tracheal allograft model, we evaluated the effect of pirfenidone, a novel antifibrotic agent, on the development of OAD.
Mice transplanted with complete MHC-mismatched tracheal allografts received pirfenidone (0.5%) in pulverized food according to different schedules: daily for the first 14 days after transplantation or daily for the duration of the study beginning on posttransplantation days 0, 5, or 10.
Mice on a continuous daily regimen of pirfenidone failed to develop evidence of chronic allograft rejection at the termination of the study (60 days). Mice receiving pirfenidone limited to the early posttransplantation period had delayed onset of OAD to 60 days. Forty percent (2/5) of mice receiving a continuous regimen of pirfenidone beginning on day 5 after transplantation had no evidence of OAD at 28 days. However, when the drug was started on day 10, all mice developed OAD by 28 days.
Our results demonstrate a delay of onset or abrogation of OAD when pirfenidone is administered in the early posttransplantation period. These findings suggest that pirfenidone is a candidate drug to be evaluated for prevention of the fibrotic changes seen in OB in human recipients of lung transplants.