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Background: Potentially harmful nonhuman leukocyte antigen antibodies have been identified in renal transplantation, including natural immunoglobulin G antibodies (Nabs) reactive to varied antigenic structures, including apoptotic cells., Methods: In this retrospective, multicenter study, we assessed Nabs by reactivity to apoptotic cells in sera collected from 980 kidney transplant recipients across 4 centers to determine their association with graft outcomes., Results: Elevated pretransplant Nabs were associated with graft loss (hazard ratio [HR] 2.71; 95% confidence interval [CI], 1.15-6.39; P   =  0.0232), the composite endpoint of graft loss or severe graft dysfunction (HR 2.40; 95% CI, 1.13-5.10; P  = 0.0232), and T cell-mediated rejection (odds ratio [OR] 1.77; 95% CI, 1.07-3.02; P  = 0.0310). High pretransplant Nabs together with donor-specific antibodies (DSAs) were associated with increased risk of composite outcomes (HR 6.31; 95% CI, 1.81-22.0; P  = 0.0039). In patients with high pretransplant Nabs, the subsequent development of posttransplant Nabs was associated with both T cell-mediated rejection (OR 3.64; 95% CI, 1.61-8.36; P  = 0.0021) and mixed rejection (OR 3.10; 95% CI, 1.02-9.75; P  = 0.0473). Finally, elevated pre- and posttransplant Nabs combined with DSAs were associated with increased risk of composite outcomes (HR 3.97; 95% CI, 1.51-10.43; P  = 0.0052) and T cell-mediated rejection (OR 7.28; 95% CI, 2.16-25.96; P  = 0.0016)., Conclusions: The presence of pre- and posttransplant Nabs, together with DSAs, was associated with increased risk of poor graft outcomes and rejection after renal transplantation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background The development of antibodies specific to HLA expressed on donor tissue (donor-specific antibodies [DSAs]) is a prominent risk factor for kidney graft loss. Non-HLA antibodies with pathogenic potential have also been described, including natural antibodies (Nabs). These IgG Nabs bind to immunogenic self-determinants, including oxidation-related antigens. Methods To examine the relationship of Nabs with graft outcomes, we assessed Nabs in blinded serum specimens collected from a retrospective cohort of 635 patients who received a transplant between 2005 and 2010 at Necker Hospital in Paris, France. Serum samples were obtained immediately before transplant and at the time of biopsy-proven rejection within the first year or 1 year after transplant. Nabs were detected by ELISA through reactivity to the generic oxidized epitope malondialdehyde. Results Univariate Cox regression analysis identified the development of post-transplant Nabs (defined as 50% increase in reactivity to malondialdehyde) as a significant risk factor for graft loss (hazard ratio, 2.68; 95% confidence interval, 1.49 to 4.82; P =0.001). Post-transplant Nabs also correlated with increased mean Banff scores for histologic signs of graft injury in post-transplant biopsy specimens. Multivariable Cox analyses confirmed Nabs development as a risk factor independent from anti-HLA DSAs (hazard ratio, 2.07; 95% confidence interval, 1.03 to 4.17; P =0.04). Moreover, patients with Nabs and DSAs had a further increased risk of kidney graft loss. Conclusions These findings reveal an association between Nabs, kidney graft injury, and eventual graft failure, suggesting the involvement of Nabs in immune mechanisms of rejection., (Copyright © 2018 by the American Society of Nephrology.)

Purpose of Review: Antibody-mediated rejection (ABMR), especially in its chronic manifestation, is increasingly recognized as a leading cause of late graft loss following solid organ transplantation. In recent years, autoantibodies have emerged as a significant component of the humoral response to allografts alongside anti-human leukocyte antigen antibodies. These include polyreactive antibodies also known as natural antibodies (Nabs) secreted by innate B cells. A hallmark of Nabs is their capacity to bind altered self such as oxidized lipids on apoptotic cells. This review provides an overview of these overlooked antibodies and their implication in the pathophysiology of ABMR., Recent Findings: New evidence reported in the past few years support a contribution of immunoglobulin (Ig) G Nabs to ABMR. Serum IgG Nabs levels are significantly higher in patients with ABMR compared with control kidney transplant recipients with stable graft function. Pretransplant IgG Nabs are also associated with ABMR and late graft loss. IgG Nabs are almost exclusively of the IgG1 and IgG3 subclasses and have the capacity to activate complement., Summary: In conclusion, Nabs are important elements in host immune responses to solid organ grafts. The recent description of their implication in ABMR and late kidney graft loss warrants further investigation into their pathogenic potential.

Background. The relationship between circulating effector memory T and B cells long after transplantation and their susceptibility to immunosuppression are unknown. To investigate the impact of antirejection therapy on T cell-B cell coordinated immune responses, we assessed IFN-γ-producing memory cells and natural antibodies (nAbs) that potentially bind to autoantigens on the graft. Methods. Plasma levels of IgG nAbs to malondialdehyde (MDA) were measured in 145 kidney transplant recipients at 5–7 years after transplantation. In 54 of these patients, the number of donor-reactive IFN-γ-producing cells was determined. 35/145 patients experienced rejection, 18 of which occurred within 1 year after transplantation. Results. The number of donor-reactive IFN-γ-producing cells and the levels of nAbs were comparable between rejectors and nonrejectors. The nAbs levels were positively correlated with the number of donor-reactive IFN-γ-producing cells (rs = 0.39, p = 0.004). The positive correlation was only observed in rejectors (rs = 0.53, p = 0.003 ; nonrejectors: rs = 0.24, p = 0.23). Moreover, we observed that intravenous immune globulin treatment affected the level of nAbs and this effect was found in patients who experienced a late ca-ABMR compared to nonrejectors (p = 0.008). Conclusion. The positive correlation found between alloreactive T cells and nAbs in rejectors suggests an intricate role for both components of the immune response in the rejection process. Treatment with intravenous immune globulin impacted nAbs. [ABSTRACT FROM AUTHOR]