DQ molecules are the principal stimulators ofde novodonor-specific antibodies in nonsensitized pediatric recipients receiving a first kidney transplant

Abstract

SummaryData on the different HLA-antibody (Ab) categories in pediatric kidney recipients developing de novo donor-specific Abs (DSA) after transplantation are scarce. We retrospectively evaluated 82 consecutive nonsensitized pediatric recipients of a first kidney graft for de novo HLA Ab occurrence and antigen specificity. At a median follow-up of 6 years, 29% of patients developed de novo DSA, while 45% had de novo non-DSA. DSA appeared at 25-month median time post-transplant and were mostly directed toward HLA-DQ antigens. Considering each HLA antigen, the estimated rate of DQ DSA (7.55 per 100 person-years) was much higher than the rates observed for non-DQ DSA. The HLA-DQ Ab recognized determinants of the DQb chain in 70% of cases, a chain in 25% of cases, and both chains in one patient. Non-DSA peaked earlier than DSA, and were largely directed against HLA class I specificities that belonged to HLA-A-and HLA-B-related cross-reacting epitope groups (CREG) in 56% of cases. Our results indicate a need for evaluating HLA-DQ compatibilities in kidney allocation, in order to minimize post-transplant development of de novo DSA, known to be responsible for antibody-mediated rejection and graft loss.

De Novo Donor-Specific HLA Antibodies Developing Early or Late after Transplant Are Associated with the Same Risk of Graft Damage and Loss in Nonsensitized Kidney Recipients

“…Moreover, comparing C1q- and C3d-binding capabilities in class I and class II dn DSAs, we demonstrated in both patient groups that C3d binding was almost exclusively a property of class II, whereas C1q binding was expressed in a similar percentage by both classes. This finding gives additional strength to previous data demonstrating that, in nonsensitized low-risk kidney recipients, class II specific and, in particular, anti-DQ de novo antibodies are the principal effectors of graft loss in all posttransplant phases [11–15, 22, 27, 30]. The equivalency of early and late dn DSA damaging capacity was further supported by the observation that the two study groups displayed a similar histological pattern of tissue graft damage.…”

“…This apparent discrepancy could be in part explained by the fact that our study exclusively analyzed nonsensitized recipients. Indeed, in a first set alloresponse condition, the ubiquitous cellular expression of class I HLA antigens within the kidney graft tissue may be balanced by the greater stimulating capability of the highly polymorphic class II molecules, in particular HLA DQ antigens [11–15, 22]. Moreover, comparing C1q- and C3d-binding capabilities in class I and class II dn DSAs, we demonstrated in both patient groups that C3d binding was almost exclusively a property of class II, whereas C1q binding was expressed in a similar percentage by both classes.…”

“…HLA typing of kidney graft recipients and donors was performed as previously described [22]. Anti-HLA class I and class II IgG antibodies were tested with a bead-based detection assay after serum EDTA treatment, to avoid underestimation of antibody MFI strength [23–25].…”

“…Anti-HLA class I and class II IgG antibodies were tested with a bead-based detection assay after serum EDTA treatment, to avoid underestimation of antibody MFI strength [23–25]. We used the LABScreen Mixed kit and the Single-Antigen Bead (SAB) assays (One Lambda Inc., CA, USA) to identify HLA class I and class II specificities [12, 22]. Screening assay results above a cut-off value of 3.0 ratio between the sample and negative control were considered positive.…”

HLA Mismatching Strategies for Solid Organ Transplantation – A Balancing Act

“…The frequency of de novo donor-specific antibody among patients matched for 2DR vs. 2DQ antigens was 9.4 and 21%, respectively. In a smaller study, Tagliamacco et al (65) found an even higher rate of posttransplant antibody following a first transplant in 82 non-sensitized pediatric renal transplant patients. In this study, 29% made donor-specific antibody de novo , 83% of which was specific for DQ.…”