Pretransplantation GAD-Autoantibody Status to Guide Prophylactic Antibody Induction Therapy in Simultaneous Pancreas and Kidney Transplantation

Background : Daclizumab and antithymocyte globulin (ATG) have been shown to reduce allograft rejection. We assessed the safety and efficacy of daclizumab or ATG prophylaxis in combination with triple immunotherapy in simultaneous pancreas-kidney transplant (SPKT) recipients.

Methods : Thirty-nine type 1 diabetic patients scheduled for primary SPKT were randomized to receive prophylactic therapy with either daclizumab or ATG. A group of 27 patients without prophylactic antibodies was used for retrospective comparison. All patients received cyclosporine and mycophenolate mofetil and gradually tapered prednisone. Autoantibodies and cellular autoreactivity were measured to assess recurrent autoreactive responses. ResultsBaseline and transplant characteristics were comparable among groups. Both daclizumab and ATG therapy resulted in a significant reduction in acute rejection episodes. The incidence of rejection episodes was significantly higher in pretransplantation GAD autoantibody-positive daclizumab-treated recipients compared with GAD autoantibody-negative or ATG-treated recipients. IA-2 islet autoantibodies showed no association with rejection. There were no significant differences between the groups for in vitro autoreactivity, clinical outcome, or functional parameters.

Conclusions : Daclizumab or ATG combined with a maintenance immunosuppressive regime consisting of cyclosporine, mycophenolate mofetil, and prednisolone were well tolerated and equally effective in reducing the incidence of acute rejection episodes in SPKT recipients. Up to 3 years, no adverse sequelae of the immunoprophylaxis or clinical and ex vivo recurrent autoimmunity were observed. We propose that the pretransplantation existence of GAD65 autoantibodies serves as a marker guiding the choice for prophylactic therapy in pancreas transplantation (read more)

Impact of de novo donor-specific HLA antibodies detected by Luminex solid phase assay after transplantation in a group of 88 consecutive living donor renal transplantations

Background : De novo donor-specific HLA antibodies (DSA) after renal transplantation are known to be correlated with poor graft outcome and the development of acute and chronic rejection. Currently, data for the influence ofde novo DSA in patient cohorts including only living donor renal transplantations (LDRT) are limited.
Methods : A consecutive cohort of 88 LDRT was tested for the occurrence of de novo DSA by utilizing the highly sensitive Luminex solid phase assay for antibody detection. Data were analyzed for risk factors of de novoDSA development and correlated with acute rejection (AR) and graft function.
Results : Patients with de novo DSA [31 (35%)] showed a trend for inferior graft function [Mean creatinine change (mg/dL/year) after the first year: 0.15 DSA (+) vs 0.02 DSA (-) (p= 0.10)] and a higher rate of AR episodes, especially in case of de novo DSA of both class I and II [6 (55%), (p= 0.05)]. Antibody mediated rejection (AMR) appeared in five patients and was significantly correlated with de novo DSA (p= 0.05).
Conclusions : Monitoring for de novo DSA after LDRT may help to identify patients at risk for declining renal function. Especially patients with simultaneous presence of de novo DSA class I and class II are at a high risk to suffer AR episodes (read more)

A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation

Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRMgenes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design (read more)

Donor specific HLA antibodies: Evaluating the risk for graft loss in renal transplant recipients with isotype switch from complement fixing IgG1/IgG3 to non-complement fixing IgG2/IgG4 anti HLA alloantibodies

HLA alloantibodies have a multitude of damaging effects on the allograft, both complement(C’) activation and Fc independent ones. To date, the clinical significance of non C’ fixing (NCF) HLA donor specific antibodies (DSA) is still unclear. In this study, we investigated whether renal transplant recipients with NCF-DSA subclasses (IgG2/IgG4,IgA1/IgA2) are at higher risk of graft loss compared to patients with exclusively C’ fixing (IgG1/IgG3). Blood samples from 274 patients were analyzed for HLA IgG and IgA subclasses using a modified single antigen bead assay. We identified 50(18.2%) patients with circulating NCF antibodies either DSA (n=17) or against third party HLA (n=33). NCF DSA were preferentially of IgG2/IgG4 isotype (11/17) and were mainly directed against HLA class II (13/17). NCF DSA were present as a mixture with strong C’ fixing IgG1/IgG3. Graft survival was similar between patients with exclusively C’ fixing antibodies and those with a mixture panel (log rang test p=0.162), and also among patients with different immunoglobulin isotype and subclasse (long rank test, p=0.732). We conclude that expansion of DSA to NCF subclasses post renal transplantation does not seem to be associated with worse graft survival as compared to the presence of exclusive C’ fixing subclasses (read more)

HLA-F and MHC Class I Open Conformers Are Ligands for NK Cell Ig-like Receptors

Killer Ig-like receptors (KIRs) are innate immune receptors expressed by NK and T cells classically associated with the detection of missing self through loss of their respective MHC ligand. Some KIR specificities for allelic classical class I MHC (MHC-I) have been described, whereas other KIR receptor–ligand relationships, including those associated with nonclassical MHC-I, have yet to be clearly defined. We report in this article that KIR3DL2 and KIR2DS4 and the nonclassical Ag HLA-F, expressed as a free form devoid of peptide, physically and functionally interact. These interactions extend to include classical MHC-I open conformers as ligands, defining new relationships between KIR receptors and MHC-I. The data collectively suggest a broader, previously unrecognized interaction between MHC-I open conformers—including prototypical HLA-F—and KIR receptors, acting in an immunoregulatory capacity centered on the inflammatory response (read more)

Clinical impact of the baseline donor-specific anti-HLA antibody measured by Luminex single antigen assay in living donor kidney transplant recipients after desensitization therapy

The aim of this study is to investigate the clinical impact of donor-specific anti-HLA-antibody (HLA-DSA) baseline levels, measured using the Luminex single-antigen assay (LSA), in living-donor kidney-transplantation (LDKT). Total 129 cases of LDKT were divided into 4 groups according to baseline mean fluorescence intensity (MFI) HLA-DSA values: Strong (n=6), >10,000; Moderate (n=8), 5,000–10,000; Weak (n=11), 1,000–5,000, Negative (n=104), <1,000. Pre-transplant desensitization (DSZ) was performed to decrease the MFI to weak or negative values before KT. Clinical outcomes in the 4 groups were compared. After DSZ, HLA-DSA decreased to weak or negative levels in all patients; Acute rejections developed more frequently in strong group (5/6 (83.3%)) compared to other three groups (P<0.05) and especially acute antibody-mediated rejection (AAMR) developed almost exclusively in strong group (4/6 (66.7%)). Strong HLA-DSA levels at baseline were more predictive of AAMR than either type of XM (complement-dependent lymphocytotoxicity or flow cytometry) in ROC analysis. Allograft function in this group showed significant deterioration during follow-up compared to the other groups. In conclusion, strong HLA-DSA levels at baseline are associated with worse allograft outcome even after successful desensitization; therefore, strict monitoring and strong maintenance immunosuppression may be required in such patients (read more)

International Kidney Paired Donation

We report a 10-way domino transplant, which was initiated in September 2009 and concluded in July 2010. The uniqueness of this chain was that it included the international exchange of kidneys between the United States and Canada. The chain was initiated by an altruistic donor and included three hospitals, four flights, one international exchange, and one pediatric recipient. The international donor and recipient procedures were performed at McGill University (Montreal, Quebec, Canada) and Johns Hopkins University (Baltimore, MD). Both organs were transported via chartered international flights with cold ischemia times of less than 6 hr, which included not only procurement and travel time but also time for customs clearance. Donor-related expenses were charged at the institution where donation occurred (read more)