Rejection In Recipients Research Articles

Tertiary Lymphoid Organs promote allograft rejection

Abstract Tertiary lymphoid organs (TLOs) are ectopic lymphoid structures that arise in non-lymphoid tissues and are frequently observed in tissue affected by non-resolving chronic inflammation. If TLOs are beneficial or detrimental in transplantation is controversial. We investigate the role of TLO and LTbR in transplantation by manipulating the LTa-LTbR pathway. Using a mouse allo kidney transplantation model, we found that preformed intragraft TLO are sufficient to precipitate rejection in recipients lacking all secondary lymphoid organs (SLO)(LTbRko). In WT recipients with a complete set of SLO, intragraft TLO accelerated rejection (MST=63 vs. 225 d). Donor grafts that cannot form TLO (LTbRko) prolonged allograft survival (MST 24 vs 11 d) in an acute kidney rejection model. Intravital imaging confirmed that T and B cell activation takes place in renal TLO upon migration of naïve T and B cells and prolonged interactions with dendritic cells. T cells produced IFNg and Confetti+/+ B cells clonally expanded within TLO. In summary, intragraft TLO are sufficient for and accelerate allograft rejection. Local immune responses are initiated and maintained in intragraft TLO, while disruption of TLO formation in the allograft leads to prolonged allograft survival. TLO support T and B cell activation as well as local DSA formation. These findings highlight the importance of TLO in local immune responses with implications for cancer, autoimmunity and transplantation.

Strategy for Clinical Setting of Co-transplantation of Mesenchymal Stem Cells and Pancreatic Islets.

Islet transplantation may be the most efficient therapeutic technique for patients with type 1 diabetes mellitus (T1DM). However, the clinical application of this method is faced with numerous limitations, including isolated islet apoptosis, recipient rejection, and graft vascular reconstruction. Mesenchymal stem cells (MSCs) possess anti-apoptotic, immunomodulatory, and angiogenic properties. Here, we review recent studies on co-culture and co-transplantation of islets with MSCs. We have summarized the methods of preparation of co-transplantation, especially the merits of co-culture, and the effects of co-transplantation. Accumulating experimental evidence shows that co-culture of islets with MSCs promotes islet survival, enhances islet secretory function, and prevascularizes islets through various pretransplant preparations. This review is expected to provide a reference for exploring the use of MSCs for clinical islet co-transplantation.

Recent advances in the immunomodulation mechanism of mesenchymal stem cell therapy in liver diseases.

Liver fibrosis, acute liver injury or liver failure, liver tumors, and immune rejection after liver transplantation are common clinical liver diseases. Immune responses are the key to determining the prognosis of liver diseases. Liver transplantation could be the last resort for patients with liver failure. However, the use of liver transplantation is limited because of the scarcity of organ donors, immunological rejection in recipients, and high cost. Mesenchymal stem cells (MSCs) are pluripotent adult stem cells with extensive anti-inflammatory and immunomodulation effects. MSCs can be effectively used for treating liver diseases but without the limitations that are associated with liver transplantation. Therefore, several clinical trials have utilized MSCs for the treatment of refractory liver diseases and the related mechanism is increasingly being elucidated. We have mainly summarized the recent studies that focus on the immunomodulation mechanism of MSC therapy in liver diseases. Further, we have presented our insights on the prospects of using MSCs in the treatment of liver diseases.

Cellular activation pathways and interaction networks in vascularized composite allotransplantation.

Vascularized composite allotransplantation (VCA) is an evolving field of reconstructive surgery that has revolutionized the treatment of patients with devastating injuries, including those with limb losses or facial disfigurement. The transplanted units are typically comprised of different tissue types, including skin, mucosa, blood and lymphatic vasculature, muscle, and bone. It is widely accepted that the antigenicity of some VCA components, such as skin, is particularly potent in eliciting a strong recipient rejection response following transplantation. The fine line between tolerance and rejection of the graft is orchestrated by different cell types, including both donor and recipient-derived lymphocytes, macrophages, and other immune and donor-derived tissue cells (e.g., endothelium). Here, we delineate the role of different cell and tissue types during VCA rejection. Rejection of VCA grafts and the necessity of life-long multidrug immunosuppression remains one of the major challenges in this field. This review sheds light on recent developments in decoding the cellular signature of graft rejection in VCA and how these may, ultimately, influence the clinical management of VCA patients by way of novel therapies that target specific cellular processes.

Gm2a as a novel regulator of CD8 +T cell threshold of activation in transplantation

Abstract Transplant patients must remain on toxic immunosuppression for life, underscoring the need to identify immunotherapeutic targets that may facilitate transplant tolerance. We recently showed that kidney transplant recipients that remained stable following withdrawal of mainstay immunosuppression exhibited increased levels of the glycosphingolipid-catabolizing protein Gm2a, specifically in CD8 +T cells, compared to patients who went on to reject their allografts. While the role of Gm2a in lysosomal glycosphingolipid degradation in neurons is well known, little is known about Gm2a function in the immune system. To investigate this, we performed skin graft surgery in WT vs Gm2a −/−mice. Results show that Gm2a deficiency significantly increased allograft rejection relative to WT counterparts. Moreover, adoptive transfer of donor-reactive WT vs. Gm2a −/−CD8 +T cells into WT hosts resulted in increased accumulation of donor-reactive T cells and accelerated allograft rejection in recipients of Gm2a −/−CD8 +T cells as compared to recipients of WT CD8 +T cells. This increased accumulation was likely due to increased proliferation, as in vitro studies revealed enhanced proliferation of CTV-labeled Gm2a −/−vs. WT CD8 +T cells. Interestingly, Gm2a −/−CD8 +T cells exhibited increased K b/SIINFEKL tetramer staining and sustained TCR expression following antigen stimulation compared to WT CD8 +T cells. Finally, Gm2a −/−CD8 +T cells exhibited increased responsiveness to low dose and low-affinity peptide compared to WT cells. In conclusion, these results identify Gm2a as a novel, CD8 +T cell-intrinsic regulator of the T cell activation threshold that directly impacts CD8 +T cell-mediated allograft rejection. Supported by grants from NIH (R01AI164716)

A RARE PRESENTATION OF MYCOPHENOLATE MOFETIL-INDUCED SEGMENTAL COLITIS MASQUERADING AS ISCHEMIC COLITIS

Mycophenolate mofetil (MMOF) is an immunosuppressive pro-drug commonly used to prevent rejection in recipients of solid organ transplants. It is hepatically converted to mycophenolic acid which then acts to reversibly inhibit inosine monophosphate dehydrogenase, thereby preventing B and T lymphocyte proliferation, B cell antibody formation, and leukocyte recruitment to sites of inflammation. Diarrhea is the most common gastrointestinal side effect of MMOF usage with up to 40% of renal transplant patients on MMOF reporting this symptom and colonoscopy not infrequently shows injurious changes that range from edema and erythema to ulcerations and diffuse colitis. Isolated reports note that colonic histopathology from patients on MMOF sometimes mimic graft-versus-host disease, inflammatory bowel disease, or ischemic colitis. However, there are very few cases that describe segmental colitis in MMOF patients. We present a rare case of a renal transplant patient presenting with MMOF-induced segmental colitis after 4 years of medication usage.

A RARE PRESENTATION OF MYCOPHENOLATE MOFETIL-INDUCED SEGMENTAL COLITIS MASQUERADING AS ISCHEMIC COLITIS

Abstract Mycophenolate mofetil (MMOF) is an immunosuppressive pro-drug commonly used to prevent rejection in recipients of solid organ transplants. It is hepatically converted to mycophenolic acid which then acts to reversibly inhibit inosine monophosphate dehydrogenase, thereby preventing B and T lymphocyte proliferation, B cell antibody formation, and leukocyte recruitment to sites of inflammation. Diarrhea is the most common gastrointestinal side effect of MMOF usage with up to 40% of renal transplant patients on MMOF reporting this symptom and colonoscopy not infrequently shows injurious changes that range from edema and erythema to ulcerations and diffuse colitis. Isolated reports note that colonic histopathology from patients on MMOF sometimes mimic graft-versus-host disease, inflammatory bowel disease, or ischemic colitis. However, there are very few cases that describe segmental colitis in MMOF patients. We present a rare case of a renal transplant patient presenting with MMOF-induced segmental colitis after 4 years of medication usage. A 52-year-old male with a history of native kidney end stage renal disease secondary to diabetic nephrosclerosis status post living unrelated kidney transplant 4 years ago from his wife presented to the emergency room for 1 week of intractable abdominal pain, vomiting, and diarrhea. His current transplant medications included atovaquone, tacrolimus, and mycophenolate mofetil. Lab work showed chronic pancytopenia with hemoglobin 10, MCV 85, platelets 58, BUN:Cr 87:5.6, and tacrolimus level 34.8. His last colonoscopy 7 years ago was unremarkable and the patient had never had an esophagogastroduodenoscopy (EGD) before. EGD while admitted showed significant erosive gastropathy with pathology showing the same. Sigmoidoscopy showed segmental colitis with punctate erythema and loss of vascularity up to the splenic flexure with the distribution of mucosal disruption suggestive of ischemic colitis. Histopathology showed fragments of colonic mucosa with patchy active cryptitis, surface erosion, distorted crypts with concurrent apoptosis and scattered eosinophils in the lamina propria – findings consistent with mycophenolate colitis. Symptomatic care was provided and the patient’s mycophenolate was tapered to cessation with complete resolution of symptoms. He was discharged with appropriate follow-up. Our case highlights a rare presentation of MMOF-induced injury whereby despite, appearance on endoscopy as a segmental ischemic colitis, histopathology was negative for ischemia but notable for MMOF-induced injury which was confirmed by symptom resolution following discontinuation of the immunosuppressive drug.. With early recognition of this pathology by clinicians with subsequent MMOF discontinuation, symptoms and prognosis can be remarkably improved. Colonoscopic image showing segmental colitis with punctate erythema and loss of vascularity. Fragments of colonic mucosa with patchy active cryptitis (star), surface erosion, mildly distorted crypts and apoptosis mainly in crypt bases with scattered eosinophils in the lamina propria, indicative of mycophenolate colitis. 400x magnification.

Abstract 10563: Differences in Donor-Derived Cell-Free DNA Levels During Allograft Rejections in Hepatitis C Positive Donor Recipient Heart Transplant Patients

Introduction: Non-invasive quantification of donor-derived cell-free DNA (dd-cfDNA) has recently been shown to correlate with endomyocardial biopsy (EMB) for diagnosis of allograft rejection in heart transplant (HTx) patients. Hepatitis C virus-positive (HCV+) donor hearts are being more utilized with comparable survival outcomes. Hypothesis: The aim of this study is to evaluate the utility of dd-cfDNA monitoring in different types of rejections in recipients of HCV+ donor hearts. Methods: We performed a retrospective review of recipients of HCV+ donor hearts between 2018-2022 with paired dd-cfDNA/GEP and EMB results. The levels of dd-cfDNA/GEP were compared in different rejection types and no rejection for patients using non-parametric comparison. CMR ISHLT ≥ Grade 2R and AMR ≥ Grade 1 from histology were considered as allograft rejection. Results: There were 17 patients who underwent heart transplant from HCV+ donor heart. There was a total of 89 paired samples with dd-cfDNA and EMB. The reason for the biopsy was mostly for routine surveillance (N=68, 76.4%). There was a total of 1 case (1.1%) of grade 2 CMR and 16 cases of pAMR (18%; 10 cases of grade 1, 6 cases of grade 2). Levels of dd-cfDNA were elevated in cases of AMR when compared to no rejection (Median: 0.24% vs. 0.12%, respectively, P<0.001; Figure 1A). There were 57 samples (78%) with dd-cfDNA reference values of <0.12%. In patients with no rejection, dd-cfDNA levels were all below 0.25%. The AUC for elevation of dd-cfDNA and allograft rejection was 0.85 [95% C.I.: 0.72-0.97; P<0.001; Figure 1B]. Conclusions: Non-invasive quantitation of dd-cfDNA levels is elevated in allograft rejection as assessed by traditional microscopy from EMB. There was no false-positive rate of dd-cfDNA in allograft rejection at a threshold of 0.25%. Further studies are indicated to study whether dd-cfDNA levels transiently increase only in the setting of allograft rejection or active hepatitis C viremia at the time of biopsy.

Endothelial failure and rejection in recipients of corneas from the same donor

ObjectiveTo determine whether patients who receive corneas from the same donor have similar risks of endothelial failure and rejection.Methods and AnalysisPatients with Fuchs endothelial dystrophy (FED) and pseudophakic bullous keratopathy...

Plasma Soluble CD146 as a Potential Diagnostic Marker of Acute Rejection in Kidney Transplantation.

Previous studies have implicated the role of CD146 and its soluble form (sCD146) in the pathogenesis of inflammatory diseases. However, the association between CD146 and acute rejection in kidney transplant patients remains unexplored. In this study, fifty-six patients with biopsy-proved rejection or non-rejection and 11 stable allograft function patients were retrospectively analyzed. Soluble CD146 in plasma was detected in peripheral blood by enzyme linked immunosorbent assay (ELISA), and local CD146 expression in graft biopsy was detected by immunohistochemistry. We found that plasma soluble CD146 in acute rejection recipients was significantly higher than in stable patients without rejection, and the biopsy CD146 staining in the rejection group was higher than that of the non-rejection group. Multivariate analysis demonstrated soluble CD146 as an independent risk factor of acute rejection. The area under the receiver operating characteristic curve (AUC) of sCD146 for AR diagnosis was 0.895, and the optimal cut-off value was 75.64 ng/ml, with a sensitivity of 87.8% and a specificity of 80.8%, which was better than eGFR alone (P = 0.02496). Immunohistochemistry showed CD146 expression in glomeruli was positively correlated with the Banff-g score, and its expression in tubules also had a positive relationship with the Banff-t score. Therefore, soluble CD146 may be a potential biomarker of acute rejection. Increased CD146 expression in the endothelial or tubular epithelial cells may imply that endothelial/epithelial dysfunction is involved in the pathogenesis of immune injury.

Gene Expression of Toll-Like Receptors 2 and 4 in Renal Transplant Rejection

Toll-like receptors are a crucial part of the innate immune system and have a pivotal role in the acquired immunity system. Studies have shown that Toll-like receptors 2 and 4 are important during the transplant process. Therefore, we analyzed the gene expression of Toll-like receptors 2 and 4 in cases of renal transplant rejection. We measured the messenger RNA expression levels of Toll-like receptors 2 and 4 in renal transplant rejection recipients compared with nonrejection recipients. We enrolled 151 deceased-donor kidney transplant recipients, whom we divided into 2 groups: 101 nonrejection recipients and 50 recipients with acute allograft rejection. We collected 3 mL of blood (treated with ethylenediaminetetraacetic acid) from each patient. Ribonucleic acid extraction and complementary DNA synthesis were conducted for all samples, and the constructed complementary DNAs were used for real-time polymerase chain reaction analysis. We measured gene expression levels of Toll-like receptors 2 and 4 in renal transplant recipients with acute allograft rejection and in recipients who did not experience acute renal allograft rejection, and the results showed that messenger RNA expression levels for both Toll-like receptors 2 and 4 were significantly increased in the acute rejection group compared with the nonrejection group. Toll-like receptors 4 and 2 could increase the risk of acute rejection after renal transplant and could be defined as a risk factor for rejection. Further studies are recommended.

To accept or reject heterospecific mates: behavioural decisions underlying premating isolation.

Premating isolation in animals involves decision-making processes that affect whether individuals accept or reject heterospecific mates. An integrative understanding of the behavioural processes underlying heterospecific acceptance can clarify the conditions under which premating isolation evolves. As an illustration, we review how Reeve's (Reeve 1989 Am. Nat.133, 407-435. (doi:10.1086/284926)) acceptance threshold model can help make sense of patterns of premating isolation in nature. This model derives a threshold trait value for acceptance for rejection of recipients of an action (e.g. mating) based on the fitness consequences of these decisions. We show that the maintenance of partial reproductive isolation can be an outcome of optimal acceptance thresholds, even in the face of reinforcement. We also use this model to clarify how the composition of multispecies communities can shape premating isolation. The acceptance threshold model can also be viewed as the behavioural underpinning of reproductive character displacement and cascading reinforcement. Finally, we highlight potential limitations of the acceptance threshold model with respect to investigating the role of sexual selection in speciation, and we propose that integration of behavioural models in speciation research will help us gain a full picture of the mechanisms underlying premating isolation. This article is part of the theme issue 'Signal detection theory in recognition systems: from evolving models to experimental tests'.

Donor apoptotic cell-based therapy for effective inhibition of donor-specific memory T and B cells to promote long-term allograft survival in allosensitized recipients.

Allosensitization constitutes a major barrier in transplantation. Preexisting donor-reactive memory T and B cells and preformed donor-specific antibodies (DSAs) have all been implicated in accelerated allograft rejection in sensitized recipients. Here, we employ a sensitized murine model of islet transplantation to test strategies that promote long-term immunosuppression-free allograft survival. We demonstrate that donor-specific memory T and B cells can be effectively inhibited by peritransplant infusions of donor apoptotic cells in combination with anti-CD40L and rapamycin, and this treatment leads to significant prolongation of islet allograft survival in allosensitized recipients. We further demonstrate that late graft rejection in recipients treated with this regimen is associated with a breakthrough of B cells and their aggressive graft infiltration. Consequently, additional posttransplant B cell depletion effectively prevents late rejection and promotes permanent acceptance of islet allografts. In contrast, persistent low levels of DSAs do not seem to impair graft outcome in these recipients. We propose that B cells contribute to late rejection as antigen-presenting cells for intragraft memory T cell expansion but not to alloantibody production and that a therapeutic strategy combining donor apoptotic cells, anti-CD40L, and rapamycin effectively inhibits proinflammatory B cells and promotes long-term islet allograft survival in such recipients.

Eosinophil‐to‐monocyte ratio is an excellent predictor of acute cellular rejection in pancreas transplant alone recipients

Serum pancreatic enzymes (serum amylase and lipase) are sensitive markers for monitoring acute rejection in pancreatic transplant recipients. However, those enzymes are not specific, as their levels are elevated in other conditions. We evaluated the eosinophil-to-monocyte ratio (EMR) in peripheral blood as a biomarker of acute rejection in the clinical setting in recipients of pancreatic transplant alone. We performed 32 cases of pancreatic transplantation alone since 2015. Nine patients were diagnosed with rejection. Serum amylase and lipase levels and eosinophil and monocytes counts were analyzed and compared retrospectively between the non-rejection and rejection groups. The serum eosinophil count, eosinophil fraction of the complete blood count, and serum amylase and lipase levels were significant predictors of rejection according to the receiver operation characteristic (ROC) curve. However, the EMR was the best indicator of rejection based on the ROC curve (area under the curve 0.918, sensitivity 100%, specificity 76.2% at the cutoff value 0.80, P<.001). The combination of EMR and the lipase level had 100% sensitivity and 90.5% specificity. The EMR is a simple and excellent predictor of acute rejection in recipients of pancreatic transplant alone.

Defining chronic rejection in vascularized composite allotransplantation-The American Society of Reconstructive Transplantation and International Society of Vascularized Composite Allotransplantation chronic rejection working group: 2018 American Society of Reconstructive Transplantation meeting report and white paper Research goals in defining chronic rejection in vascularized composite allotransplantation.

Objectives:This report summarizes a collaborative effort between the American Society of Reconstructive Transplantation and the International Society of Vascularized Composite Allotransplantation to establish what is known about chronic rejection in recipients of vascularized composite allografts, with an emphasis on upper extremity and face transplants. As a picture of chronic rejection in hand and face vascularized composite allografts emerges, the results will be applied to other types of vascularized composite allografts, such as uterine transplantation.Methods:The overall goal is to develop a definition of chronic rejection in vascularized composite allografts so that we can establish longitudinal correlates of factors such as acute rejection, immunosuppressive therapy, de novo donor-specific antibody and trauma/infection and other external factors on the development of chronic rejection. As Dr Kanitakis eloquently stated at the 2017 International Society of Vascularized Composite Allotransplantation meeting in Salzburg, “Before we can correlate causative factors of chronic rejection, we have to define what chronic rejection in VCA is.”Results:The first meeting report was presented at the sixth Biennial meeting of the American Society of Reconstructive Transplantation in November 2018. Based on collaborative efforts and descriptions of clinical cases of chronic rejection in vascularized composite allograft recipients, a working definition of chronic rejection in vascularized composite allografts with respect to overt functional decline, subclinical functional decline, histologic evidence without functional decline, and normal allograft function in the absence of histologic evidence of chronic rejection is proposed.Conclusions:It is the intent of this collaborative working group that these working definitions will help to focus ongoing research to define the incidence, risk factors and treatment regimens that will identify mechanisms of chronic rejection in vascularized composite allografts. As with all good research, our initial efforts have generated more questions than answers. We hope that this is the first of many updates.

Generics in transplantation medicine: Randomized comparison of innovator andsubstitution products containing mycophenolate mofetil .

Objective: Mycophenolate mofetil (MMF) is widely used as an immunosuppressant for the prophylaxis of acute organ rejection in recipients of solid organ transplants. Materials and methods: We have compared, in healthy subjects, the pharmacokinetics of mycophenolic acid when MMF was administered in the form of the innovator product CellCept (F. Hoffmann-La Roche Ltd.) or one of three commercially available generics, Renodapt (Biocon Ltd.), Mycept (Panacea Biotec), or Cellmune (Cipla Ltd.). The study was powered to detect a 20% difference in mean formulation performance measures, but not to formally evaluate bioequivalence. Geometric mean ratios of maximum concentrations (Cmax) and areas under plasma concentration-time curves were calculated. Results: Comparing generics against each other, the differences in point estimates of the geometric mean ratios of Cmax of two of the comparisons were either borderline within (Renodapt/Cellmune) or clearly outside (Mycept/Cellmune) a region of 80 – 125% around the reference mean, indicating that bioequivalence between these generics may be difficult to show. Conclusion: Physicians in the field of transplantation should be aware of the potential risk of altering the therapeutic outcome when switching from one preparation of MMF to another. ClinicalTrials.gov identifier: NCT02981290.

Is There a Temporal Relationship Between Trough Whole Blood Tacrolimus Concentration and Acute Rejection in the First 14 Days After Kidney Transplantation?

There are inconsistent findings regarding the relationship between trough whole blood tacrolimus concentration (TAC C0) and acute kidney rejection in recipients undergoing TAC therapeutic drug monitoring (TDM). However, studies have not always assessed TAC C0 at the time of rejection or accounted for variability in hematocrit. Therefore, this study aimed to investigate the temporal relationship between TAC C0 and acute rejection, including when accounting for variation in hematocrit. For 38 recipients who developed biopsy-proven acute rejection (BPAR) in the first 14 days after kidney transplantation, daily TAC C0 from TDM and hematocrit was collected from case notes. Differences in log10-transformed TAC C0 between the day of BPAR (log Cr), 1 day before BPAR (log Cr-1), and 2 days before BPAR (log Cr-2) and the combined median concentrations for the days preceding these (log Cprior) were examined by repeated-measures analysis of variance with Dunnett post hoc testing. Generalized linear mixed-effects regression (glmer) examined the ability of TAC C0 to predict acute rejection episodes with and without controlling for hematocrit. Log Cr-1 [mean difference (95% confidence interval) = -0.13 (-0.21 to -0.048), post hoc P = 0.002] and log Cr [-0.13 (-0.24 to -0.025), post hoc P = 0.013] were significantly lower than log Cprior. TAC C0 was a significant (P = 0.0078) predictor of rejection episodes (area under the receiver operating characteristic curve = 0.79) only in glmer models accounting for variability in hematocrit. In recipients who developed BPAR, there was a significant temporal relationship between TAC C0 and BPAR incidence under TAC TDM that may not be detected in cross-sectional studies, especially if variability in hematocrit is not addressed. This supports a TAC C0-rejection relationship, which differs between recipients, and may explain why some recipients do or do not experience rejection within or below the TDM range, respectively. However, studies with larger sample sizes are needed to confirm this finding.

Comparison of clinical outcome of induction immunosuppressive therapy with thymoglobulin and standard therapy in kidney transplantation; a randomized double-blind clinical trial

Introduction: Thymoglobulin is a lymphocyte-depleting polyclonal antibody, administered for induction therapy at the time of kidney transplantation to reduce the risk of acute allograft rejection. The appropriate dosage and duration of therapy is controversial. The higher dosages are associated with infection and malignancy. Objectives: In this study efficacy and safety of lower dosage (in comparison with previous studies) of thymoglobulin in kidney transplant recipients was evaluated. Patients and Methods: In this clinical trial, 106 adult kidney transplant recipients, were randomized before transplantation in two groups (case and control). The case group (53 patients) were received induction therapy with thymoglobulin (1.5 mg/kg/d for 3 days) and the control group (53 patients) were received non-induction regiment. Delayed graft function (DGF), glomerular filtration rate (GFR), acute allograft rejection and thymoglobulin complications were evaluated during the first post-transplantation year. Results: Around 106 kidney transplant recipients were enrolled (71 or 66.98% deceased donor) to the study. No significant statistical differences were found in GFR at the time of discharge from hospital (P=0.399) and at 1 year (P=0.851) and acute allograft rejection (P= 0.304) between two groups. Graft survival (73.5% in case group versus 81.1% in control group, P=0.392) at month 12th was similar among groups. Additionally, no significant differences of acute allograft rejection in recipient from deceased or living donor between two groups were detected. There was a higher incidence of DGF in the control group (26.4%) than the thymoglobulin group (5.8%) and the difference was statistically significant (P= 0.004). Thrombocytopenia (17% versus 49.1%, P&lt;0.001) and leukopenia (11.3% versus 50.9%, P&lt;0.001) were also significantly higher in the case group. Conclusion: While the incidence of DGF was reduced in thymoglobulin group, the short-term acute allograft rejection rate was not reduced compared to the control group. However, our results require further consideration with larger samples

Association of HLA-G Polymorphisms in the 3‘UTR Region and Soluble HLA-G with Kidney Graft Outcome

ABSTRACTBackground: Human leukocyte antigen G (HLA-G) belongs to nonclassical HLA I molecule involving in the suppression of immune response. Besides its profound effect to induce fetal tolerance, HLA-G expression has been associated with allograft acceptance. For the regulation of HLA-G levels, polymorphic sites within the 3′ untranslated region (3′UTR) are of crucial importance. The aim of the study was to analyze the association between several HLA-G 3′UTR variants (+3003T/C, +3010C/G, +3027C/A, +3035C/T, +3142G/C, +3187A/G, and +3196C/G), soluble HLA-G (sHLA-G) level, and kidney graft outcome in the Slovak Caucasian population.Methods: We investigated 69 kidney transplant recipients (45 males, 24 females) of age 27–65 years. Out of this group, 37 recipients developed acute rejection that was biopsy proven. Recipient’s plasma was obtained at 1 day before transplantation and analyzed by ELISA. The HLA-G 3′UTR polymorphisms were typed by direct sequencing.Results: In the recipients with stable allograft function, significantly higher values of sHLA-G were found in the homozygous +3010GG, +3142CC, +3187GG, and +3196CC carriers in comparison to the acute rejection recipients (P = 0.01-0.05).Conclusion: The study demonstrated genetic association between HLA-G 3′UTR variants and sHLA-G level in kidney recipients leading to graft acceptance. We suggest to monitor the pretransplantation sHLA-G level as additional marker to predict kidney graft outcome. Abbreviations: AMR: Antibody-mediated rejection; APC: antigen-presenting cell; CD: cluster of designation; del: deletion; HLA: human leukocyte antigen; ILT: immunoglobulin-like transcript; ins: insertion; KIR: killer-cell immunoglobulin-like receptor; NK: natural killer; sHLA-G: soluble HLA-G; SNP: single nucleotide polymorphism; TCMR: T cell-mediated rejection; URR: upstream regulatory region; UTR: untranslated region

Natural Killer Cells Exhibit an Activated Phenotype in Peripheral Blood Mononuclear Cells of Renal Allograft Rejection Recipients: A Preliminary Study.

A growing body of evidence has revealed the role of innate immune cells in transplantation; however, the nature of natural killer cell involvement in rejection is still elusive. Here, we aimed to determine the impact of natural killer cell activities in acute and chronic renal transplant rejection. This preliminary case-control study included 63 participants: 19 were patients with kidney allograft rejection (8 patients with acute rejection and 11 patients with chronic rejection) and 44 comprised the control group (22 patients who had well-functioning grafts posttransplant and 22 healthy subjects). In addition to natural killer cell frequency, we also measured intracellular interferon-? production and surface expression of CD107a as cytotoxic activity using flow cytometry. We observed a significant increase in CD107a expression (P = .021) in patients with acute rejection versus those with well-functioning grafts. Moreover, production of interferon-? in patients with chronic rejection was significantly increased compared with patients with well-functioning grafts (P = .003). Finally, natural killer cell frequency was decreased in patients with rejection versus control groups; however, this reduction was not statistically significant. These findings suggest that the increase in natural killer cell cytotoxicity is correlated with rejection in kidney transplant recipients and might be considered as a predictive marker in prevalence of graft rejection.