Monday, April 28, 2014

Early Acute Antibody-Mediated Rejection of a Negative Flow Crossmatch 3rd Kidney Transplant with Exclusive Disparity at HLA-DP.

Donor-specific alloantibodies (DSA) to HLA-DP may cause antibody-mediated rejection (AMR), especially in re-transplants. We describe the immunization history of a patient who received 3 kidney transplants; the 3rd kidney was completely matched except at DPA1 and DPB1. Prior to the 3rd transplant, single antigen bead analysis (SAB) showed DSA reactivity against DPA1 shared by the 1st and 3rd donors, but B and T flow crossmatch (FXM) results were negative. Within 11 days the 3rd transplant underwent acute C4d+ AMR which coincided with the presence of complement (C1q)-binding IgG1 DSA against donor DPA1 and DPB1. Using HLAMatchmaker and SAB, we provide evidence that eplet (epitope) spreading on DPA1 and eplet sharing on differing DPB1 alleles of the 1st and 3rd transplants was associated with AMR. Since weak DSA to DPA1/DPB1 may induce acute AMR with negative FXM, donor DPA1/DPB1 high resolution typing should be considered in sensitized patients with DP-directed DSA (read more)

Saturday, April 19, 2014

First-in-Human Study of the Safety and Efficacy of TOL101 Induction to Prevent Kidney Transplant Rejection

TOL101 is a murine IgM mAb targeting the αβ TCR. Unlike other T cell targets, the αβ TCR has no known intracellular signaling domains and may provide a nonmitogenic target for T cell inactivation. We report the 6-month Phase 2 trial data testing TOL101 in kidney transplantation. The study was designed to identify a dose that resulted in significant CD3 T cell modulation (<25 T cell/mm3), to examine the safety and tolerability of TOL101 and to obtain preliminary efficacy information. Thirty-six patients were enrolled and given 5–10 daily doses of TOL101; 33 patients completed dosing, while three discontinued after two doses due to a self-limiting urticarial rash. Infusion adjustments, antihistamines, steroids and dose escalation of TOL101 reduced the incidence of the rash. Doses of TOL101 above 28 mg resulted in prolonged CD3 modulation, with rapid recovery observed 7 days after therapy cessation. There were no cases of patient or graft loss. Few significant adverse events were reported, with one nosocomial pneumonia. There were five biopsy-confirmed acute cellular rejections (13.9%); however, no donor-specific antibodies were detected. Overall TOL101 was well-tolerated, supporting continued clinical development using the dose escalating 21–28–42–42–42 mg regimen (read more)

Wednesday, April 2, 2014

Immunosuppressants and alloimmunization against red blood cell transfusions

Background : Patients receiving red blood cell (RBC) transfusions are at risk of developing alloantibodies against donor RBC antigens. The risk of alloimmunization is dependent on the number of units administered and patient's genetic predisposition, but has also been suggested to be modulated by a patient's clinical profile. Our aim was to examine whether immunosuppressants suppress the development of clinically relevant RBC antibodies.
Study Design and Methods : A two-center case-referent study was performed where case patients and control patients were sampled from all consecutive patients (17,750 patients) who had received their first and subsequent RBC transfusions in a 5-year period in the study centers. Cases were all patients with a first detected RBC alloantibody preceded by negative antibody screens. Control patients were two-to-one matched to the case patients on the number of RBC transfusions. Logistic regression analysis was used to examine the association between immunosuppressant exposure and the subsequent occurrence of RBC alloimmunization.
Results : A total of 156 case patients and 312 control patients in the study received a median of six transfusions (interquartile range, 3-11). Among the total study population, 207 patients received immunosuppressive therapy, with 142 patients receiving only corticosteroids, four receiving only other immunosuppressants, and 61 receiving both. The incidence of alloimmunization among patients using immunosuppressants was lower than among other patients receiving RBCs (adjusted relative rate, 0.55; 95% confidence interval, 0.34-0.91).
Conclusion : Our findings support a considerably lower risk of alloimmunization with the use of immunosuppressive medications (read more)

Autoimmune Neutropenia After Kidney Transplantation: A Disregarded Entity of Posttransplant Neutropenia

Background : Neutropenia is common after kidney transplantation and is associated with an increased incidence of infections. Drug toxicities are the main causes of posttransplant neutropenia (PTN), mainly related to immunosuppressive drugs as mycophenolic acid (MPA) and anti-infectious agents, but some PTN remain unexplained.
Methods : Between January 2012 and January 2013, cultures of autologous granulocytic progenitors from bone marrow aspirate were performed in two patients with unexplained severe neutropenia.
Results : Both patients’ serum inhibited granulocytic differentiation while granulocytic differentiation was normal with the control serum. Similar inhibition of differentiation of granulocytic progenitors from a control marrow was observed with the patients’ serum as compared with the control serum. Moreover, in both cases intravenous immunoglobulins allowed full neutrophil count recovery. Other usual etiologies of acquired neutropenia including systemic drug toxicity, infection, and autoimmune disease were excluded. As frequently observed in adult immune neutropenia, granulocyte autoantibodies were absent in both cases. Owing to biological and clinical results, we concluded that an autoimmune mechanism was responsible for neutropenia. The levels of MPA, which is known to interact with tacrolimus, were not measured in our patients. However, the persistence of neutropenia more than 70 days after withdrawal of MPA did not support this hypothesis.
Conclusion : Autoimmune neutropenia should be considered in kidney transplant recipients in case of persistent unexplained neutropenia as it allows effective treatment and avoids the withdrawal of important immunosuppressive and anti-infectious treatments (read more)