Soluble Co-Signaling Molecules Predict Long-Term Graft Outcome in Kidney-Transplanted Patients

Abstract

Co-signaling molecules are responsible for full T-cell activation after solid organ transplantation. Their increased expression can lead to the release of a soluble form that can modulate the immune response post-transplantation. We analyzed the presence of co-signaling molecules (sCD30, sCD40, sCD137, sCTLA-4, sCD80, sCD28, sCD40L, sPD-1, and sPD-L1) in serum from kidney-transplanted patients (n = 59) obtained at different times (before transplantation, and 15 days, 3 months and 1 year post-transplantation) and their contribution to graft outcome was evaluated using principal component analysis. Before transplantation, high levels of soluble co-signaling molecules (mainly sCD30, sCD137 and sCD40) were detected in all patients. These molecules were modulated soon after receiving an allograft but never attained similar levels to those of healthy controls. A signature based on the determination of six soluble co-stimulatory (sCD30, sCD40, sCD137 and sCD40L) and co-inhibitory (sPD-1 and sPD-L1) molecules at 3 months post-transplantation allowed a group of patients to be identified (27.12%) with a worse long-term graft outcome. Patients with high levels of soluble molecules showed a progressive and gradual deterioration of kidney function (increased creatinine and proteinuria levels and decreased estimated glomerular filtration rate) over time and a higher risk of graft loss at 6 years post-transplantation than patients with low levels of these molecules (62.55% versus 5.14%, p<0.001). Thus, our data show an aberrant expression of soluble co-signaling molecules in kidney-transplanted patients whose quantification at 3 months post-transplantation might be a useful biomarker of immune status and help to predict long-term graft evolution.

Peritransplant Soluble CD30 as a Risk Factor for Slow Kidney Allograft Function, Early Acute Rejection, Worse Long-Term Allograft Function, and Patients’ Survival

“…Lower posttransplant levels of sCD30 in individual patients, in its turn, can be explained by lower pretransplant levels of this biomarker, as our analysis show moderate correlation between them. On the contrary to our results, several groups found the association of higher pre- and posttransplant sCD30 with worse allograft function [ 5 , 30 , 31 , 35 ] up to 2 years [ 35 ] and 3 years [ 5 ] or reported the absence of such a link [ 19 , 33 ]. Thus, more studies are needed to elucidate the relationships between sCD30 and late allograft function.…”

“…The association of higher pretransplant sCD30 [ 9 , 10 , 15 , 16 , 25 , 28 , 29 ] and posttransplant sCD30 [ 27 , 28 , 30 – 32 ] with increased risk of graft loss and worse graft survival was found in most published studies, including several large multicenter studies [ 9 , 10 , 32 ]. However, these results were not confirmed by other authors [ 5 , 19 , 33 ].…”

“…Most studies included only recipients of cadaver graft [ 9 , 10 , 14 , 25 ] or living-donor graft [ 5 , 11 , 28 ]. Sources describing the relationship of sCD30 with long-term kidney allograft function are few and contradictory [ 5 , 19 , 30 , 31 , 33 , 35 ]. Finally, the effect of sCD30 on the survival of recipients is poorly described in the literature [ 4 , 9 , 25 , 26 , 34 ], which argues for the necessity of further study.…”

Identification of programmed cell death 1 and its ligand in the testicular tissue of mice

“…13 Dendritic cells, 14,15 regulatory T cells (Tregs), 16 and alternatively activated (M2) macrophages 17 in the interstitial space help convert the environment to an immune-skewing milieu that is advantageous for developing germ cells. 22 The sPD-L1 can be detected in physiological and pathological conditions and is mainly produced by matrix metalloproteinase (MMP) cleavage from the cell surface. However, the breakdown of this elaborate physiological status can lead to orchitis (an etiological factor of male infertility), followed by impaired androgen synthesis and diminished spermatogenesis.…”

“…21 Aside from their membrane-bound forms, PD-1 and PD-L1 also have soluble forms: soluble PD-1 (sPD-1) and soluble PD-L1 (sPD-L1). 22 The sPD-L1 can be detected in physiological and pathological conditions and is mainly produced by matrix metalloproteinase (MMP) cleavage from the cell surface. 23 Both molecules can regulate the PD-1/PD-L1 pathway in that sPD-1 can inhibit negative signaling mediated by the PD-1/PD-L pathway in activated CD8 + T cells 24 while sPD-L1 has the opposite effect.…”