Non-HLA Antibodies to Immunogenic Epitopes Predict the Evolution of Chronic Renal Allograft Injury

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105

107

The initial contact point between a recipient's immune system and a transplanted graft is the vascular endothelium. Clinical studies suggest a pathogenic role for non-HLA antiendothelial cell antibodies (AECAs) in allograft rejection; however, evidence linking AECAs of known specificity to in vivo vascular injury is lacking. Here, we used high-density protein arrays to identify target antigens for AECAs isolated from the sera of recipients of kidney transplants experiencing antibody-mediated rejection in the absence of donor-specific HLA antibodies. Four antigenic targets expressed on endothelial cells were identified: endoglin, Fms-like tyrosine kinase-3 ligand, EGF-like repeats and discoidin I-like domains 3, and intercellular adhesion molecule 4; the first three have been implicated in endothelial cell activation and leukocyte extravasation. To validate these findings, ELISAs were constructed, and sera from an additional 150 renal recipients were tested. All four AECAs were detected in 24% of pretransplant sera, and they were associated with post-transplant donorspecific HLA antibodies, antibody-mediated rejection, and early transplant glomerulopathy. AECA stimulation of endothelial cell cultures increased adhesion molecule expression and production of inflammatory cytokines: regulated on activation, normal T cell expressed and secreted PDGF and RESISTIN. These correlations between in vitro experiments and in vivo histopathology suggest that AECAs activate the vascular endothelium, amplifying the alloimmune response and increasing microvascular damage. Given the growing number of transplant candidates, a better understanding of the antigenic targets, beyond HLA, and mechanisms of immune injury will be essential for improving long-term allograft survival.

Section: Protein Microarray Analysesmentioning

confidence: 99%

Endothelial Cell Antibodies Associated with Novel Targets and Increased Rejection

Jackson¹,

Sigdel

Delville

et al. 2015

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105

107

“…5 Nevertheless, ongoing allograft rejection in HLA identical transplant recipients and patients without detectable anti-HLA Abs to donor HLA antigens (DSA) supports an additional pathogenic role for graft injury by non-HLA antigens, such as protein kinase-z, and MHC class 1-related chain A (MICA). [6][7][8][9] In adult renal transplantation, Terasaki 10 and Terasaki and Cai 11 have shown that preformed and de novo post-transplant production of DSAs correlates with a higher risk of acute rejection (AR) and reduced 1-year graft survival. The impact of the humoral response has not been well studied in the pediatric transplantation.…”

mentioning

confidence: 99%

The Clinical Impact of Humoral Immunity in Pediatric Renal Transplantation

Chaudhuri

Ozawa

Everly

et al. 2013

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The development of anti-donor humoral responses after transplantation associates with higher risks for acute rejection and 1-year graft survival in adults, but the influence of humoral immunity on transplant outcomes in children is not well understood. Here, we studied the evolution of humoral immunity in lowrisk pediatric patients during the first 2 years after renal transplantation. Using data from 130 pediatric renal transplant patients randomized to steroid-free (SF) or steroid-based (SB) immunosuppression in the NIH-SNSO1 trial, we correlated the presence of serum anti-HLA antibodies to donor HLA antigens (donorspecific antibodies) and serum MHC class 1-related chain A (MICA) antibody with both clinical outcomes and histology identified on protocol biopsies at 0, 6, 12, and 24 months. We detected de novo antibodies after transplant in 24% (23% of SF group and 25% of SB group), most often after the first year. Overall, 22% developed anti-HLA antibodies, of which 6% were donor-specific antibodies, and 6% developed anti-MICA antibody. Presence of these antibodies de novo associated with significantly higher risks for acute rejection (P=0.02), chronic graft injury (P=0.02), and decline in graft function (P=0.02). In summary, antibodies to HLA and MICA antigens appear in approximately 25% of unsensitized pediatric patients, placing them at greater risk for acute and chronic rejection with accelerated loss of graft function. Avoiding steroids does not seem to modify this incidence. Whether serial assessments of these antibodies after transplant could guide individual tailoring of immunosuppression requires additional study.

“…Antibodies to endothelial cell antigens other than HLA antigens have been previously detected in KTRs, particularly in relation to CMV infection. [42][43][44][45] However, because no binding of IgG from nonsensitized sera was found by flow cytometry on IVEC, lysis of these cells with this serum suggests the presence of unknown factors other than IgG able to induce gd T-cell cytolytic potential. This assay could therefore be interesting to identify new factors involved in endothelial cell damage.…”

Section: Discussionmentioning

confidence: 88%

Cytomegalovirus-Responsive γδ T Cells

Bachelet

Couzi

Pitard

et al. 2014

Human cytomegalovirus infection in transplant recipients has been associated with adverse renal allograft outcome and with a large gd T-cell response, but whether both mechanisms are connected is unknown. We previously showed that most expanded circulating cytomegalovirus-responsive gd T cells express the Fcgreceptor CD16, suggesting that gd T cells may participate in allograft lesions mediated by donor-specific antibodies through antibody-dependent cellular cytotoxicity. Here, we show that cytomegalovirus-specific CD16 pos gd T cells can perform antibody-dependent cellular cytotoxicity against stromal cells coated with donor-specific antibodies in vitro. In vivo, graft-infiltrating gd T cells localized in close contact with endothelial cells only in patients who experienced cytomegalovirus infection and were more frequent within peritubular capillaries and glomeruli from antibody-mediated acute rejections than within those from T cell-mediated acute rejections. Finally, a persistently increased percentage of circulating cytomegalovirus-induced gd T cells correlated inversely with the 1-year eGFR only in kidney recipients with donor-specific antibodies. Collectively, these data support the conclusion that cytomegalovirus-induced gd T cells are involved in, and may serve as a clinical biomarker of, antibody-mediated lesions of kidney transplants. Moreover, these findings offer a new physiopathologic link between cytomegalovirus infection and allograft dysfunction in recipients with donor-specific antibodies.