scholarly journals Fisiopatologia del rigetto acuto e cronico

2019 ◽  
Vol 31 (2) ◽  
pp. 128-132
Author(s):  
Aris Tsalouchos ◽  
Maurizio Salvadori
Keyword(s):  
Immune System ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Graft Loss ◽  
Graft Function ◽  
Adaptive Immune System ◽  
Immunosuppressive Drugs ◽  
Antibody Mediated Rejection ◽  
Pathologic Features ◽  
Activation Antigen

Allograft rejection is defined as tissue injury produced by the effector mechanisms of the alloimmune response, leading to deterioration of graft function. There are two types of rejection: T-cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR). Both types of rejection can be early or late, fulminant or indolent, as well as isolated or concomitant and can share pathologic features on biopsy. The immune response to an allograft is an ongoing dialogue between the innate and adaptive immune system, which if unresolved will lead to rejection of the transplanted cells, tissues, or organs. Activation of elements of the innate immune system, triggered by tissue injury sustained during cell isolation or organ retrieval and ischemia reperfusion, will initiate and amplify the adaptive response. T cells require a minimum of two signals for activation: antigen recognition and co-stimulation. Antibody-mediated rejection triggered by alloantibody binding and complement activation is increasingly recognized as a significant contribution to graft loss. Even though one component of the immune system may dominate and lead to rejection, this is usually multifactorial, resulting from the integration of multiple mechanisms. Identifying the molecular pathways that trigger rejection facilitates the identification of targets for the development of immunosuppressive drugs.

scholarly journals Review: Ischemia Reperfusion Injury—A Translational Perspective in Organ Transplantation

2020 ◽  
Vol 21 (22) ◽  
pp. 8549
Author(s):  
André Renaldo Fernández ◽  
Rodrigo Sánchez-Tarjuelo ◽  
Paolo Cravedi ◽  
Jordi Ochando ◽  
Marcos López-Hoyos
Keyword(s):  
Reperfusion Injury ◽  
Organ Transplantation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Graft Loss ◽  
Surgical Techniques ◽  
Immunosuppressive Drugs ◽  
Donation Process ◽  
End Stage ◽  
Significant Injury

Thanks to the development of new, more potent and selective immunosuppressive drugs together with advances in surgical techniques, organ transplantation has emerged from an experimental surgery over fifty years ago to being the treatment of choice for many end-stage organ diseases, with over 139,000 organ transplants performed worldwide in 2019. Inherent to the transplantation procedure is the fact that the donor organ is subjected to blood flow cessation and ischemia during harvesting, which is followed by preservation and reperfusion of the organ once transplanted into the recipient. Consequently, ischemia/reperfusion induces a significant injury to the graft with activation of the immune response in the recipient and deleterious effect on the graft. The purpose of this review is to discuss and shed new light on the pathways involved in ischemia/reperfusion injury (IRI) that act at different stages during the donation process, surgery, and immediate post-transplant period. Here, we present strategies that combine various treatments targeted at different mechanistic pathways during several time points to prevent graft loss secondary to the inflammation caused by IRI.

scholarly journals Acute recurrent pericarditis: from pathophysiology towards new treatment strategy

Heart ◽  
2020 ◽  
Vol 106 (14) ◽  
pp. 1046-1051 ◽  
Author(s):  
Patrice Cacoub ◽  
Cindy Marques
Keyword(s):  
Immune System ◽  
Inflammatory Response ◽  
Interleukin 1 ◽  
Treatment Algorithm ◽  
Real Life ◽  
Adaptive Immune System ◽  
Immunosuppressive Drugs ◽  
Controlled Study ◽  
Recurrent Pericarditis ◽  
Receptor Antagonists

Acute idiopathic or so-called viral pericarditis is a frequent and usually benign disease, although recurrences are frequent. Data strongly suggest the presence of underlying autoinflammatory and/or autoimmune disorders. It has been reported that there is an inflammatory response of the innate immune system typical of ‘autoinflammatory diseases’, predominantly mediated by interleukin-1 (IL-1). This may result from the activation of the inflammasome by a cardiotropic virus or a non-specific agent. The inflammatory response of the adaptive immune system, typical of ‘autoimmune diseases’—mainly mediated by autoantibodies or autoreactive T lymphocytes—seems also involved as anti-heart or anti-intercalated disk autoantibodies were associated with a higher number of recurrences and hospitalisations. Current guidelines recommend that aspirin/non-steroidal anti-inflammatory drugs for a few weeks should be associated to colchicine for 6 months in recurrent pericarditis. In refractory cases, low-dose corticosteroids or immunosuppressive drugs have been proposed with limited efficacy. Growing evidences suggest a place of IL-1 receptor antagonists in the treatment of recurrent pericarditis. Many retrospective studies, one recent randomised placebo-controlled study and data of a real-life large international registry showed the good efficacy of anakinra with a good safety profile. Other IL-1 receptor antagonists showed promising results (canakinumab, rilonacept). However, IL-1 receptor antagonists’ position in the treatment algorithm of recurrent pericarditis needs further evaluation in larger prospective clinical trials to replicate initial findings as well as to assess safety, cost-effectiveness and long-term efficacy.

scholarly journals Multiplex gene analysis reveals T-cell and antibody-mediated rejection-specific upregulation of complement in renal transplants

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eva Vonbrunn ◽  
Tajana Ries ◽  
Stefan Söllner ◽  
Janina Müller-Deile ◽  
Maike Büttner-Herold ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Inflammatory Cells ◽  
Antibody Mediated Rejection ◽  
Transplant Patients ◽  
Markers Of Inflammation

AbstractIn renal transplantation, complement is involved in ischemia reperfusion injury, graft rejection and dysfunction. However, it is still unclear how induction of complement and its activation are initiated. Using allograft biopsies of a well-characterized cohort of 28 renal transplant patients with no rejection (Ctrl), delayed graft function (DGF), acute T-cell-mediated (TCMR) or antibody-mediated rejection (ABMR) we analyzed differences in complement reaction. For that mRNA was isolated from FFPE sections, quantified with a multiplex gene expression panel and correlated with transplant conditions and follow-up of patients. Additionally, inflammatory cells were quantified by multiplex immunohistochemistry. In allograft biopsies with TCMR and ABMR gene expression of C1QB was 2-4 fold elevated compared to Ctrl. In TCMR biopsies, mRNA counts of several complement-related genes including C1S, C3, CFB and complement regulators CFH, CR1 and SERPING1 were significantly increased compared to Ctrl. Interestingly, expression levels of about 75% of the analyzed complement related genes correlated with cold ischemia time (CIT) and markers of inflammation. In conclusion, this study suggest an important role of complement in transplant pathology which seems to be at least in part triggered by CIT. Multiplex mRNA analysis might be a useful method to refine diagnosis and explore new pathways involved in rejection.

scholarly journals P1758TOCILIZUMAB TREATMENT IN DSA POSITIVE ANTIBODY MEDIATED REJECTION AMONG KIDNEY TRANSPLANT RECIPIENTS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Orsolya Cseprekal ◽  
Adrienn Marton ◽  
Sara Molnar ◽  
Attila Patonai ◽  
Attila Fintha ◽  
...  
Keyword(s):  
Kidney Transplant ◽  
Graft Loss ◽  
Graft Function ◽  
Treatment Protocol ◽  
Case Series ◽  
Class I ◽  
Antibody Mediated Rejection ◽  
Series Analysis ◽  
Transplant Patients ◽  
Kidney Transplant Patients

Abstract Background and Aims Pretransplant or de novo donor specific antibodies (DSA) may lead to active or chronic active antibody mediated rejection (a and cABMR) as leading cause of graft loss after kidney transplantation. There is no treatment protocol approved for ABMR. Anti Il-6 tocilizumab (TCZ), inhibitor of DSA production, is a potential approach to stabilize kidney allograft function, however, evidence based results are not available. In our retrospective case series analysis, we assessed the changes in DSA and eGFR during and at the end of treatment with TCZ. Method In our single center case series analysis, 10 kidney transplant patients with biopsy proven ABMR (aABMR 6, cABMR 4, age 43±10.5ys, 6 males, time since transplantation 18(2-119)months, 7 first transplant, serum creatinine 224±80 umol/L at baseline) were studied between January 2017 – June 2019. Total plasma exchange (PE) (5x) was followed by TCZ (8 mg/kg, 1x monthly for 6 months) in case of a and cABMR. Intravenous immunoglobulin (IVIG, 1gr/kg) was added in case of aABMR. Routine laboratory parameters and DSA were reported retrospectively. Results 6 aABMR patients completed the treatment protocol. Class I DSA decreased significantly (MFI 4457(635-14084) vs. 877(595-5678); p=0.007), but Class II DSA remained the same during the treatment (MFI 4725 (586-17615) vs. 8097 (671-14636) p=NS). eGFR of aABMR patients and 1 cABMR patient were stabilized. 3 cABMR patients returned to dialysis. Reversible elevation of liver transaminases were detected in three patients. There was no any serious adverse event recorded. Conclusion The opportunely timed TCZ seems to be effective in reducing Class I DSA and stabilize graft function in patients with aABMR. Further studies are needed to prove the long-term efficacy and the exact role of TCZ in cABMR among kidney transplant patients.

scholarly journals Sensitization and Desensitization in Vascularized Composite Allotransplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Dimitrios Moris ◽  
Linda C. Cendales
Keyword(s):  
De Novo ◽  
Tissue Injury ◽  
Graft Loss ◽  
Soft Tissue Injury ◽  
Tissue Loss ◽  
Current Evidence ◽  
High Dose ◽  
Vascularized Composite Allotransplantation ◽  
Antibody Mediated Rejection ◽  
Current Evidence Base

Vascularized composite allotransplantation (VCA) is a field under research and has emerged as an alternative option for the repair of severe disfiguring defects that result from severe tissue loss in a selected group of patients. Lifelong immunosuppressive therapy, immunosuppression associated complications, and the effects of the host immune response in the graft are major concerns in this type of quality-of-life transplant. The initial management of extensive soft tissue injury can lead to the development of anti-HLA antibodies through injury-related factors, transfusion and cadaveric grafting. The role of antibody-mediated rejection, donor-specific antibody (DSA) formation and graft rejection in the context of VCA still remain poorly understood. The most common antigenic target of preexisting alloantibodies are MHC mismatches, though recognition of ABO incompatible antigens, minor histocompatibility complexes and endothelial cells has also been shown to contribute to rejection. Mechanistically, alloantibody-mediated tissue damage occurs primarily through complement fixation as well as through antibody-dependent cellular toxicity. If DSA exist, activation of complement and coagulation cascades can result in vascular thrombosis and infarction and thus rejection and graft loss. Both preexisting DSA but especially de-novo DSA are currently considered as main contributors to late allograft injury and graft failure. Desensitization protocols are currently being developed for VCA, mainly including removal of alloantibodies whereas treatment of established antibody-mediated rejection is achieved through high dose intravenous immunoglobulins. The long-term efficacy of such therapies in sensitized VCA recipients is currently unknown. The current evidence base for sensitizing events and outcomes in reconstructive transplantation is limited. However, current data show that VCA transplantation has been performed in the setting of HLA-sensitization.

scholarly journals Antiapoptotic Molecule Survivin in Transplantation: Helpful or Harmful?

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Sara Assadiasl ◽  
Mohammad Javad Mousavi ◽  
Aliakbar Amirzargar
Keyword(s):  
Immune System ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Adaptive Immune System ◽  
The Other ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Protein ◽  
Advantages And Disadvantages ◽  
Adaptive Immune ◽  
Apoptosis Protein

Survivin, an antiapoptotic molecule from inhibitor of apoptosis protein (IAP) family, is most known for its implication in cancer as there are some efforts to apply it for diagnostic as well as therapeutic purposes in oncology. On the other hand, it could be a useful molecule to be positively targeted when trying to save tissue and promote cells viability. Since protecting the allograft from ischemia reperfusion injury and inflammation-induced damage is a considerable objective in transplantation, it is reasonable to take advantage from antiapoptotic agents like survivin in order to achieve this goal. However, survivin’s potential ability to induce malignancies makes some concerns about its use in clinic. The other barrier is this molecule’s involvement in lymphocytes development and proliferation which might increase the risk of graft rejection due to adaptive immune system overactivation. In this review we summarize the few studies carried out about survivin’s effect on graft survival and probable advantages and disadvantages of its overexpression in transplantation.

scholarly journals Does Rabbit Antithymocyte Globulin (Thymoglobuline®) Have a Role in Avoiding Delayed Graft Function in the Modern Era of Kidney Transplantation?

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Lluís Guirado
Keyword(s):  
Lower Risk ◽  
Antithymocyte Globulin ◽  
Ischemia Reperfusion ◽  
Graft Loss ◽  
Graft Function ◽  
Delayed Graft Function ◽  
Kidney Graft ◽  
Transplant Recipients ◽  
Rabbit Antithymocyte Globulin ◽  
Risk Patients

Delayed graft function (DGF) increases the risk of graft loss by up to 40%, and recent developments in kidney donation have increased the risk of its occurrence. Lowering the risk of DGF, however, is challenging due to a complicated etiology in which ischemia-reperfusion injury (IRI) leads to acute tubular necrosis. Among various strategies explored, the choice of induction therapy is one consideration. Rabbit antithymocyte globulin (rATG [Thymoglobuline]) has complex immunomodulatory effects that are relevant to DGF. In addition to a rapid and profound T-cell depletion, rATG inhibits leukocyte migration and adhesion. Experimental studies of rATG have demonstrated attenuated IRI-related tissue damage in reperfused tissues, consistent with histological evidence from transplant recipients. Starting rATG intraoperatively instead of postoperatively can improve kidney graft function and reduce the incidence of DGF. rATG is effective in preventing acute rejection in kidney transplant recipients at high immunological risk, supporting delayed calcineurin inhibitor (CNI) introduction which protects the graft from early insults. A reduced rate of DGF has been reported with rATG (started intraoperatively) and delayed CNI therapy compared to IL-2RA induction with immediate CNI in patients at high immunological risk, but not in lower-risk patients. Overall, induction with rATG induction is the preferred choice for supporting delayed introduction of CNI therapy to avoid DGF in high-risk patients but shows no benefit versus IL-2RA in lower-risk individuals. Evidence is growing that intraoperative rATG ameliorates IRI, and it seems reasonable to routinely start rATG before reperfusion.

scholarly journals Renal transplant patients with preformed anti-HLA antibodies: early biopsy findings and clinical outcomes

2020 ◽  
Vol 42 (2) ◽  
pp. 201-210
Author(s):  
Marcos Vinicius de Sousa ◽  
Ricardo de Lima Zollner ◽  
Marilda Mazzali
Keyword(s):  
Renal Function ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Kidney Graft ◽  
Kidney Transplant Recipients ◽  
Hla Antibodies ◽  
Antibody Mediated Rejection

Abstract Introduction: Renal fibrosis is the end point of a process that begins at transplant, with ischemia reperfusion and early inflammation, and progresses over time with immunological and non-immunological phenomena. Early identification of morphological markers and intervention could improve graft function and survival. Objective: to evaluate the correlation between intensity and specificity of pre-transplant anti-HLA antibodies and kidney allograft pathology in order to identify early risk factors or markers of allograft dysfunction. Methods: A retrospective cohort of kidney transplant recipients with pre-transplant anti-HLA antibodies who underwent graft biopsy within the first two years post-transplant was divided into two groups according to the specificity of anti-HLA antibodies: nonspecific (non-DSA, n = 29) and specific (DSA+, n = 16). Kidney graft pathology, renal function, and proteinuria were analyzed. Results: general characteristics were similar in both groups, except for the higher dose of thymoglobulin in DSA+ group (p < 0.05). The non-DSA group had higher scores for glomerulosclerosis, interstitial inflammation (i) and interstitial fibrosis (ci) (p < 0.05) and higher incidence of cell-mediated acute rejection. No statistical difference in incidence of antibody-mediated rejection, renal function, and proteinuria was observed during follow up. Discussion and conclusions: the difference in inflammation scores and interstitial fibrosis may be associated to the higher incidence of acute cell-mediated rejection and polyomavirus nephropathy in the Non-DSA group. We also should take into account the protective effect of higher doses of thymoglobulin, reducing ischemia reperfusion injury in the DSA+ group. The short follow-up might have been insufficient to detect long-term changes in allograft tissue, renal function, and proteinuria.

scholarly journals The Role of Mitochondria in Immune-Cell-Mediated Tissue Regeneration and Ageing

2021 ◽  
Vol 22 (5) ◽  
pp. 2668
Author(s):  
Yu-Jih Su ◽  
Pei-Wen Wang ◽  
Shao-Wen Weng
Keyword(s):  
Mitochondrial Dna ◽  
Immune System ◽  
Tissue Regeneration ◽  
Intracellular Signaling ◽  
Immune Cell ◽  
Tissue Injury ◽  
Energy Requirement ◽  
Human Mesenchymal Stem Cells ◽  
Adaptive Immune System

During tissue injury events, the innate immune system responds immediately to alarms sent from the injured cells, and the adaptive immune system subsequently joins in the inflammatory reaction. The control mechanism of each immune reaction relies on the orchestration of different types of T cells and the activators, antigen-presenting cells, co-stimulatory molecules, and cytokines. Mitochondria are an intracellular signaling organelle and energy plant, which supply the energy requirement of the immune system and maintain the system activation with the production of reactive oxygen species (ROS). Extracellular mitochondria can elicit regenerative effects or serve as an activator of the immune cells to eliminate the damaged cells. Recent clarification of the cytosolic escape of mitochondrial DNA triggering innate immunity underscores the pivotal role of mitochondria in inflammation-related diseases. Human mesenchymal stem cells could transfer mitochondria through nanotubular structures to defective mitochondrial DNA cells. In recent years, mitochondrial therapy has shown promise in treating heart ischemic events, Parkinson’s disease, and fulminating hepatitis. Taken together, these results emphasize the emerging role of mitochondria in immune-cell-mediated tissue regeneration and ageing.

scholarly journals Influence of Persistent Inflammation in Follow-Up Biopsies After Antibody-Mediated Rejection in Kidney Transplantation

2021 ◽  
Vol 8 ◽  
Author(s):  
Gaston J. Piñeiro ◽  
Enrique Montagud-Marrahi ◽  
José Ríos ◽  
Pedro Ventura-Aguiar ◽  
David Cucchiari ◽  
...  
Keyword(s):  
Graft Survival ◽  
Cox Regression ◽  
Graft Loss ◽  
Graft Function ◽  
Kidney Graft ◽  
Cox Regression Analysis ◽  
Antibody Mediated Rejection ◽  
Persistent Inflammation ◽  
Increased Risk

Background: Despite recent advances in immunosuppression treatment, antibody-mediated rejection (ABMR) remains the leading cause of kidney graft loss. Information about prognostic markers and the efficacy of treatment is scarce.Methods: Retrospective study with kidney recipients diagnosed an active ABMR from January 1, 2004 to December 31, 2019 to explore the influence of persistent inflammation in follow-up biopsies on graft survival after ABMR treatment.Results: About 116 patients were included. Active ABMR were treated with a combination of plasma exchange (PE), intravenous immunoglobulin (IVIg), rituximab, and steroids. At 6 months of treatment, 63 (54.3%) patients presented a stabilization or improvement in kidney-graft function. The effectiveness varied depending on the timepoint of the presentation between transplantation and rejection, which is lower for those with late ABMR (63 vs. 21% for early vs. late ABMR, respectively). Ninety patients (77%) underwent a control biopsy after ABMR treatment, from which 46 (51%) responded to the treatment. Microvascular inflammation (MVI) persisted in 64 (71%) biopsies, whereas tubulitis persisted in 17 (19%) biopsies. Death-censored graft survival at 1 year was significantly lower in patients with persistent MVI (86% vs. 95% without persistent MVI, P = 0.002), or with persistent tubulitis (44% vs. 66% without tubulitis, P = 0.02). In the Cox Regression analysis, the persistence of MVI [hazard ratio (HR), 4.50 (95%CI, 1.35–14.96), P = 0.01] and tubulitis [HR 2.88 95%CI (1.24–6.69), P = 0.01) in follow-up biopsies significantly increased the risk of graft failure.Conclusion: Persistent inflammation in follow-up biopsies after ABMR treatment was associated with an increased risk of graft loss, even without meeting Banff rejection criteria.Study Registration: Agencia Española de Medicamentos y Productos Sanitarios (AEMPS): 14566/RG 24161. Study code: UTRINM-2017-01.

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