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The immunologic risk associated with donor-specific antibodies (DSA) against Class II human leukocyte antigens (HLA) in kidney transplant (KTx) recipients is unclear. The aim of this study was to determine the outcome of KTx when DSA was detected only against HLA Class II. To isolate the impact of anti-Class II DSA, we retrospectively analyzed 12 KTx recipients who at baseline had a positive B-cell flow cytometric crossmatch (FXM) and a negative T-cell FXM. Using alloantibody specification analysis, 58.3 (712) had DSA against donor Class II and 41.7 had no demonstrable DSA. Biopsy-proven AMR occurred in 57 (47) in the Class IIgroup and 0 in the Class II?group (p > 0.05). Peritubular capillaries stained positive for C4d in 86 (67) of the Class IIpatients and in 40 (25) of the Class II?patients (p > 0.05). One patient in the Class IIgroup lost their graft at 3 months to accelerated transplant glomerulopathy, while all other grafts were functioning 3-37 months posttransplant despite the persistence of anti-Class II DSA. We conclude that KTx recipients with clearly defined anti-Class II DSA are at risk for humoral rejection suggesting that desensitization andor close posttransplant monitoring may be needed to prevent AMR.

The authors report a successful fully robotic trans‐abdominal transplant nephrectomy.

Antibody production by normal plasma cells (PCs) against human leukocyte antigens (HLA) can be a major barrier to successful transplantation. We tested four reagents with possible activity against PCs (rituximab, polyclonal rabbit antithymocyte globulin (rATG), intravenous immunoglobulin (IVIG) and the proteasome inhibitor, bortezomib) to determine their ability to cause apoptosis of human bone marrow-derived PCs and subsequently block IgG secretion in vitro. IVIG, rituximab and rATG all failed to cause apoptosis of PCs and neither rituximab nor rATG blocked antibody production. In contrast, bortezomib treatment led to PC apoptosis and thereby blocked anti-HLA and antitetanus IgG secretion in vitro. Two patients treated with bortezomib for humoral rejection after allogeneic kidney transplantation demonstrated a transient decrease in bone marrow PCs in vivoand persistent alterations in alloantibody specificities. Total IgG levels were unchanged. We conclude that proteasome activity is important for PC longevity and its inhibition may lead to new techniques of controlling antibody production in vivo.

We examined the course of donor-specific alloantibody (DSA) levels early after transplant and their relationship with acute humoral rejection (AHR) in two groups of positive crossmatch (XM) kidney transplant recipients: High DSA group-41 recipients with a baseline T- or B-cell flow crossmatch (TFXM, BFXM) channel shift ?300 (molecules of equivalent soluble fluorochrome units (MESF) of approximately 19?300) who underwent pretransplant plasmapheresis (PP), and Low DSA group-29 recipients with a baseline channel shift <300 who did not undergo PP. The incidence of AHR was 39 (1641) in the High DSA group and 31 (929) in the Low DSA group. Overall, mean DSA levels decreased by day 4 posttransplant and remained low in patients who did not develop AHR. By day 10, DSA levels increased in patients developing AHR with 92 (2325) of patients with a BFXM >359 (MESF of approximately 34?000) developing AHR. The BFXM and the total DSA measured by single antigen beads correlated well across a wide spectrum suggesting that either could be used for monitoring. We conclude that AHR is associated with the development of High DSA levels posttransplant and protocols aimed at maintaining DSA at lower levels may decrease the incidence of AHR.

Donor-specific alloantibody presents a major barrier to the successful transplantation of kidneys and hearts. However, the study of alloantibody production has been hampered by both an inadequate source of antibody-secreting cells (ASCs) and a paucity of assays to determine their function. We describe two new assays that allow for the determination of the frequency and specificities of allo-ASCs in humans using purified HLA as targets. These assays demonstrated allo-ASCs in the CD138fraction of the bone marrow, but not in peripheral blood. Alloantibody specificities in these assays correlated well with those detected in the serum suggesting that bone marrow-derived ASCs are indeed a major source of alloantibody in vivo. However, ASCs for a specific HLA antigen were rare with an estimated frequency of only 12 × 106marrow cells. Pretransplant treatment in vivowith multiple plasmaphereses and low-dose IVIG alone or in combination with rATG had no effect on ASC number or alloantibody production. These techniques allow for the study of allospecific ASCs and provide a method to test the potential efficacy of agents on alloantibody production in vivo.

Rituximab, intravenous immunoglobulin (IVIG) and rabbit antithymocyte globulin (rATG) all have been suggested to have an effect on antibody producing cells, however, supporting data are lacking. To assess the impact of these agents on splenic B-cell populations in vivo, we retrospectively examined 25 spleens removed from patients treated with these agents as part of desensitization protocols in either ABO incompatible or positive crossmatch living donor kidney transplantation. These were compared to control (CTL) spleens removed for trauma. CTLs and spleens removed at transplant after multiple pretransplant plasmaphereses (PP) plus low-dose IVIG showed similar large numbers of naïve B cells (CD20and CD79), plasma cells (CD138) and memory B cells (CD27cells). Adding rituximab to this PPIVIG regimen reduced the number naïve B cells, but had no effect on memory or plasma cells. Combination treatment (PPIVIG, rituximab and rATG) showed a trend toward the reduction of CD27cells, but again plasma cells were unchanged. We conclude that none of these protocols reduces splenic plasma cells in vivo. PPlow-dose IVIG does not alter splenic B cells, but the addition of rituximab decreases mature B cells. Memory B cells may be affected by combination therapy including rATG and requires further study.