Transplant Immunology in Nephrology: Immunonephrologist
Over the past 20 years, significant advancements in transplant immunology have been made, yet challenges remain in areas such as reducing immunosuppression and enhancing graft tolerance. Strengthening immunological education and funding for nephrologists is crucial for further progress. Immunonephrology, akin to interventional nephrology, should be integral to nephrology training, focusing on immunity’s role in kidney disease and optimal immunomodulation strategies. Tools like HLA typing and managing donor-specific antibodies (DSA) are vital. T-cell and antibody-mediated rejections are central issues, involving complex immune mechanisms. Recent methods for early detection and prognosis of graft rejection include transcriptomic, epigenetic, proteomic, metabolic, and cellular biomarkers. Current treatments for graft rejection include various antibody removal and neutralization methods, with thymoglobulin showing promise as an induction agent. Complement system inhibitors also present new therapeutic avenues. In this episode, we will discuss the role of immunonephrology in kidney transplantation. The learning objectives include understanding immunological damage and therapeutic applications in kidney transplants.
Dr. Jigar shrimali
Hello everyone, my name is Dr. Jigar shrimali. I am a consultant, nephrologist and transplant physician at Breena's Kidney Hospital, Ahmedabad and Nariya. Today's discussion is related to Translion immunology in nephrology. So particularly the role of immuno nephrologist that is the discussion of point for today. So if we discuss about it, the discussion pertaining to immuno nephrology, why it is so important for us. So for other we have few learning objectives for this module. So this is about the basics of immunology and immunomodated damage in kidney transplantation. We need to understand the role of immunomodating in kidney transplantation. We need to understand the therapeutic application of immuno nephrology in the kidney transplantation. So if we discuss it one by one, let's have the first section and that is about the immunomodated damage in kidney transplantation. In last 20 years, there is significant advantage in Breena transplant immunology over a period of time and it contributed to the primary objective of immunologist and clinical researcher. Despite this significant achievement, there are some areas still need progress such as defining non-imniozibiamic for active rejection, continuous reduction of immunosuppression and the extension of graph-cybauer and graph-tolerance. These are the points where we need further growth. Now what is the role of immuno nephrologists in this multiple advances in immuno nephrology? So immunology is not a major component of the nephrologist's curriculum and the kidney disease. Do not represent the key interest for the immuno. So if you do see both the side, there are some issues. So therefore, the nephrology community must make a strong commitment to strengthen the immunological background of the future generation of the nephrologists through education or by providing adult funding opportunities. So this will help multiple advances in immuno nephrology on several parts leading to earlier diagnosis and intervention which will help us and will increase the long-term success. Additionally, it can lead to development of more sustainable and patient-friendly module for renal replacement therapy that would be novel intervention to delay the chronic kidney disease progression and there would be improvement in the management of the kidney disease. Let's discuss about the role of immuno-lologists in advancing the research and improving patient outcome in the kidney transplantation related to the field of immuno nephrology. So immuno nephrology or kidney immuno-loud will become a key species of spatiality of nephrology like for what we are doing with intervention nephrology or we are doing with ultrasound in nephrology. Same like this, we need immuno nephrology knowledge in our branch. The aim would be to understanding the role of immunity in the pathophysiology of the kidney disease and defining the optimum immuno-model treatment study for immuno-broad group compatibility. What we need, hLA typing, donor-specific antivolus. Now the testing for the ABO compatibility involves two methods used to reduce the circulatory ABO antibody type which includes plasma pharases and immuno-adception. Now the goal to achieve the titres is generally less than 1 raise to it or 1 raise to 32, depend on the various centers their practices. Now retuxima is used as an adjoint therapy to reduce the antibody production and has replaced this clinic to me that was their year's ban. So as per the annual report by scientific registry of the transplant recipient, if 5 are allograp survival for disease donor kidney transplantation is 77% with but with zero hLA and 67% with 6 hLA mismatch. So we can see the difference. So in testing of DSA which are the antibodies in the recipient's ear that is specific to the donor and if this are present in very high titres it is considered as a contraindication for the transplantation donor point of view and the strength of this DSA is measured by MFI. MFI is mean chlorosomes intensive play a role in ABMR antibody mediated rejection. So this pathogenic donor specific antibodies can be desensitized using methods like plasma pharases or by retuxima, high dose IV, immunoglobulin and with various combinations. Generally DSA more than 5000 MF is a contraindication for transplantation and again we can see in the cadaver scoring more than 5000 is considered as a point for allocation. So let's discuss about the pathophysiological mechanism of T cell mediated graph rejection in the kidney transplantation. So T cell plays a crucial role in graph rejection by directly recognizing and responding to the foreign HLA molecule through TCF that is T cell receptor MHC major histocompatibility complex interaction which is mainly responsible for the chronic rejection of the most issues. Subscuantly T cell and cells of innate immune function synergistically to reject the LO. So in addition this TLR that is at all like receptor and the complement system which are compound of innate immunity are also centered with the grafting. Pattern recognition receptors are expressed on the outdoor cell membrane specially on the antigen presenting cells such as the antibiotics cell or microphysic cognition pathogen associated molecule pattern that is PAMP to elicit the immune inanimate. Now the legation of APC with antigen initiation intracellular signal transduction cascade that leads to nuclear factor kapabi NMK kapabi activation and the upregulation of adhesion molecule and post-stimulatory molecule cytokine and that are essential to immune activation. So the T cell mediated rejection is characterized by i number of CD56 and CD57 cells within the interstitial compound and it is associated with interstitial inflammation and double aisles both characterized of T cell mediated radiation. So according to the future allorative T cell recognition on donor cell or the donor derived antigen presented on recipient cell. So this recipient cells readily present intact donor MHC peptide complexes and damages cells release signal that activate the T cell. Now about mechanism of graft rejection in anti-modimidated rejection. Generally 22 30% of the acute rejection episodic kidney trans plantation it involves humoral compound which is mainly mediated by reform or newly developed anti-d donor antibodies against HLA and endothelial cells and ABON. The presence of this circulating DSA donor specific antibodies and C4D deposition in the paratubular capillaries are the key feature of ABO. Now C4D deposition in paratubular capillaries and glomerular containing mononuclear cells is currently the base single matter for complement fixing and antibody interaction with vascular endothelium. Now this HLA antibodies are considered the risk factor for hyperacute, acyrel and chronic allograph rejection. The pathophysiological mechanisms of this BCL mediated rejection and production of immunoglobulin gamma antibodies depend on the specific interaction between CD4 T cells and B cells. This clonal expansion and differentiation of activated B cells give rise to the short lived plasma blast that migrate to the screen or long live plasma cell that reside in the bone marrow and secret donor specific antibodies responsible for mediating vascular injury as we are able to see in the figure. So if we discuss about the graft rejection mediated by a natural killer cell in kidney transplantation, granular graft rejection CD56, DM, CD16, NK cells play a significant role in promoting antibody dependent cellular toxicity, ADCC, against the graft by interacting with DSS, bound to the graft endothelial cell and thereby it leads to ABM. Conversely, the cells are involved in T cell mediated rejection through secretion of interferon gamma pro-inflammatory molecule that is pro-inflammatory molecule. So NK cell can also contribute to the transplant tolerance by directly killing the donor derived dendritic cell and producing high level of interleukin type. However, there are mutual antagonism or temporary definition of the contribution of NK cell and T regulatory cells to the induction of transplant tolerance immunosuppressive drug can be modified or rather immunosuppressive drugs can modulate the phenotype of NK cell which can still respond to stimulation. So additionally immunosuppression can reduce the number of NK cell after the transplantation thus this modification or rather monitoring the number and function of NK cell in transplant patients under specific immunosuppressive regimen is very crucial to predict and control the onset of infection and your blood. So if you focus on mechanism of monocyte derived, yellow regulation, yellow recognition and not signaling mediated graft rejection in kidney transplantation. So in kidney transplant monocyte derived yellow recognition mechanism that involves the mobilization of recipient monocyte derived macrophages in response to ishemaic profusion injury with trickers the release of chemotherapy. The allograft infiltration and accumulation of monocyte or macrophages have been proposed as a potential diagnostic marker out of the transplant rejection as series 68 macrophage infiltration was significantly elevated in amm and associated with graft failure. So the notch signaling is a highly conserved cell to cell communication pathway which is triggered by notch ligand receptor interaction between adjacent cells. The release plays essential role during T cell development and is the central mediator of T cell alloriate weight. So short term inhibition of individual notch ligand in the peri transplant period has long slalasting protective effect. On a block head of delta like notch ligand as shown to dampen the both cellular and humoral rejection in the heart allograft model. So therefore it has been proposed that targeting element of the notch pathway could provide a new therapeutic approach to prevent the allograft rejection by reducing pro-inflammatory cytocate production by the T cell effector T cell and it enhance the functional T regulatory cell. The emerging model of notch signaling is a central regulator of the alloriate activity versus tolerance we can see in the figure. So now let's discuss about the comparison of the HLA at the molecular level. But traditionally HLA whole antigen mismatch only evaluate whether the do not and the recipient's molecule are the same or different. The issue is that some mismatches, some mismatch HLA molecules are nearly identical while others mean the very desperate information ignored with traditional HLA mismatch assessment. Fortunately the relative difference can be captured and quantified by HLA molecular mismatch comparison. For instance say for HLA D-R1 and HLA D-R1 are the HLA antigen of the patient and the donor respective. For molecular comparison it was found that the donor shared 3 out of 5 HLA athletes with the recipient. This means that the donor and 2 mismatch athletes that were different from those in the recipients HLA and D-R1. So if we discuss the concept of HLA athletes which is being considered as a new currency for measuring HLA compatibility, the current method of defining HLA compatibility is not that adequate in assessing the immunological risk associated with translantation. So this is because the conventional HLA does not accurately quantify the risk. Therefore there is a need for a better representation of immunological risk associated with HLA compatibility. This first method is the HLA which is emerging as a new HLA compatibility currency. It provides a more precise measure of the immunological risk involved in translantation compared to what we are doing this conventional HLA match routinely. So let us have a look on emerging trends of the athletes matching in the Kineo translantation. When assessing HLA mismatch in Kineo translantation, athlete mismatches are evaluated by examining the small patches of surface exposed immunization on HLA molecules. Rather than focusing on antigen mismatches for molecular mismatching or athlete mismatch, load analysis is currently the best tool available for risk stratification at the population level. But utilization of this mismatch can facilitate the delivery of the personalised and decision medicine by enhancing the selection of suitable organs and by that way would be able to tailor the immunosuppression accordingly. Because in India obviously we all know that the infection is a major issue so it would be really helpful. Now the studies have shown that athlete mismatches in HLA-DQ confer significant risk for DNO-DS of formation, graph rejection, graph failure after the transplantation and mismatch is in other low-cations to have laser impact. Now the second section is roll-up immunomonitoring in Kineo translantation. In this section we will discuss the E-roll of DNO-specific HLA antibodies in hyperactive rejection. The clinical frequency of DSA in translantation varies widely ranging from S-low S, O-POS and to maybe 50%. However, it is well established that pre-existing or DNO-DS has an unfavorable effect on graph outcome in solid organ transplantation. A study found that adverse events in the early post-transland period have a negative impact on the long-term graph survival regardless of the time of the rock and how this negative impact is not observed if good graph function is achieved by end of the third month in post-transland period. So let us understand the respect of HLA-DQ sensitization in Kineo translantation has been found to elicit strong antibody production than the initial transplantation which can increase the risk of early graph growth. In Hooman pregnancy that is an inevitable event that scientists sensitize them to HLA-DQ antigen. Sensitization due to pregnancy has a significant impact on the development of the HLA-DQ class 1 and class 2 antivolt. The incidence of the HLA-B antibody development was higher in patients sensitize by pregnancy compared to those sensitize by after-transland or transferable. Despite even proper ABO antigen prostimaging, the patient would experience transfusion reaction when they receive multiple bird supply and in blood transfusion the leading cause of mortality is trialing that is transfusion related acute lung injury. Although the transfusion is purely immunogenic, persistent HLA arrow sensitization in use induction requires multiple transfusion that is the problem. So now we will discuss the association of HLA mismatch with graph survival and mortality in Kineo translant. HLA mismatch in a critical prognostic factor that affect both graph and the recipient survival in translant. So HLA-DQ mismatch has a substantial impact on the graph survival of the recipient whereas the HLA-A mismatch has a minor insignificant impact on graph survival. Each incremental increase in HLA mismatch have been found to significantly associatively the higher risk of overall graph failure, death sensor graph failure and all cause mortality specifically HLA-DQ mismatch. Having found to be significantly associated with a 12% higher risk of overall graph failure while HLA-A mismatch is associated with 6% higher risk of overall graph failure. So we can see how DIA impact on this. Let us look at the conventional method of detecting HLA antibody using cell bases as well. So the CDC cross-med test is used to screen the preform antibodies in the recipient that may react against the donor immediately. This stage can be either a T cell or B cell cross-med. In a T cell cross-med, T lymphocytes are isolated from the donor and mixed with the serum from the resident. If preform antibodies are present in the recipient, they recognize the HLA class 1 molecule and bind to them. Upon addition of complement, the cell undergolysis and the diet that penetrates the LISe cell is used to detect the number of days. In case of the recipient's enough does not contain any antibody that bind to clearly imposed out of the donor, the complement will remain inactive and the cell will undergo LISe as a result no diet will penetrate to the cell and the test will be considered as a negative. Now we will discuss the conventional method of detecting HLA antibody using solid base assay. The HLA can be immobilized on solid structure, surface and its presence can be detected by using 3D front method. The first method is a lysine which involves incubating the HLA mount serum of the patient on the plastic surface to detect the antibody. If the antibody binds the antigen, the enzyme link immunoglobulin G produces the colored product. If there are no anti-HLA antibody, the potential serum, the anti-humid IGG cannot be attained and it is washed away and no colored product is produced at the time. The second method is a implode bead dependent cross which uses fluorescent latex HLA beads to detect IGG M or IGG antibody against both HLA class 1 and class 2. With complement fixation, where is multiple HLA antigen can be located on the base. So the third method is Luminex single antigen bead assay which use HLA molecule immobilized on 100 polystyrene microsphere with flow sunlight. The serum is incubated with the microspheres coated with this HLA molecule and anti-vortis are detected using flow cytometry and mean fluorescence intensity MFI quantification. MFI value greater than 5000 is considered a contraindication for the translantation. So let's look at the virtual cross and epitope analysis in kidney translantation. The virtual cross match is a technique used to assess the immunological compatibility between the recipient and the potential node by analyzing their HLA typing and recipient own anti-HLA antibody without using donors lymphosec. The CDC and flow cytometry cross match have been used to assess the compatibility between kidney translant recipient and donor without viable cell using single antigen bead assay and high resolving HLA method. Although the usefulness and safety of virtual cross match have been reported, there is still controversy regarding whether it is can replace the physical cross match or not. So there are various aspects related to physical cross match and virtual cross match. Out of that nothing is superior to another method specifically that we can see. Now this epitope analysis is a method used to infer that targeted epitopes from the SAV assay reaction pattern to SSA HLA compatibility. The principle of epitope analysis that involves picking up the bits from mean fluorescence intensity MFI exceeding the cutoff value based on the results of the single antigen bead assay. For say for example bead number 1 to 5 and 8 in the figure we can see can be considered. Next possible epitope analysis by L8 on the positive bits are selected. For epitope analysis estimate epitopes against the antibody that decagonizes the low MFI HLA and complementing SAV and virtual cross require high resolution typing and manual judgment. Now we will discuss the transcripting epigenetic and proteomic biomass for early detection and prognosis of chronic kidney transplant rejection. Recent advances in high throughout technology have greatly improved the management of CKD and chronic kidney transplant rejection through different biomass. The transcript of this transcriptomic biomass because generally through high throughput gene or transcripting profiling utilizing microarray and next generation gene sequence that is NGS technology. This gene expression profiling can identify gene signatures associated with FTA chronic rejection, graph failure and providing a higher predictive capacity than baseline clinical variables and clinical and pathological variability. This IIFTA has been identified as a reliable non-invasive biomarker in unison. So the epigenetic biomass is derived from the epigenetic changes and regulators controlling the relevant gene expression and function during biological processes. So epigenetic modification such as DNA, mutilation, microarray, and histone modification and chromatic remodeling complexes can be utilized to predict the outcome and detect the chronic alograft dysfunction in transplantation. This is proteomic biomass and non-invasive and can be scored by employing high throughput proteomic techniques such as liquid chromatography, mass spectroscopy, LCMS, isobaric tech for relative and absolute quantification that is ITRAQ, protein, microarray and lead base amino acid. A CXC motif, this chemokine line that is CXEL line and CXC motif chemokine 10 that is CXEL 10 are reliable by biomarkers for subclinical alograft rejection and can guide post-transplant management. So let us look at the meta-bolemic and cellular biomarker for early detection and prognosis of chronic kidney transplant rejection. So this metabolic biomass are rapidly emerging in organ transplantation studies using meta-boleomics, involving the comprehensive analysis of all the metabolic in the single biological sense. Compared to the proteomic or transcriptomic marker, metabolic biomarker offers more promising to reflect the cellular function and have shown promising in detecting rejection and other organics. This urine, nori meta-boleomics has shown promising results in improving the detection of borderline TCMR and active ACMMR in children. Another potential biomarker is the measurement of ATB generation by mitosis-stimulated CD4 infoside using FDA approved immuno assay that could be effective in transplant residue. Cellulobiac marker are derived from specific cells T-cell or NCAS or cellular compounds that can be used to identify and monitor the rejection. Quantifica, find this yellow reactive CD8 T-cells as potential cellular biomarker of rejection or tolerance has a garnered significant attention. Single cell sequencing technology have rapidly developed and have been evolved as a powerful tool for safe and single cell sequencing technology has the advantage of identifying variability in individual cells, detecting even a smaller number of cells and by that way creating detailed cell map and making it a powerful tool for biomarker discovery in organ transplant study. In the chronic kidney transplant rejection group, a novel sub-population of bio-fibroblast in fibroblast which expresses the collagen and extracellular matrix compound has been identifiable as a potential cellular biomarker. Now what does KD go say? As per the KD go 2020 clinical practical guidelines that provide the recommendation for assessment and management of the potential candidate for disease or living donor kidney transplant. This guidelines suggest severe immuno-logical assessment to be performed in clinical practice this includes communicating all sensitize events or clinical events that can impact the pay to the HLA lab performing HLA antibody testing at transplant evaluation at regular interval before transplantation and after a sensitizing event or a clinical event that can impact the payer event. In addition it is recommended that HLA antibody testing will perform using solid phase Ss. The guideline also suggests that performing HLA typing of the candidate at evaluation using molecular method. The candidate need not be routinely tested for non-HLA events for complement binding HLA antibodies. Additionally, the guideline becomes informing the candidate about their SS2D transplantation based on blood type and by histocompillative testing results. Before desensitization, SS2 or larger disease is the donor pool kidney exchange program and our desensitization antibody avoidance such as kidney care donation or disease donation or donor acceptable mismatch allocation to be considered. Now, our section is therapeutic application of immuno-nefology in kidney transplantation. So now we will discuss the current treatment to tackle the alograv rejection kidney transplantation. There are several treatment modalities that have been employed for the treatment of the IVAMA including antibody removal or neutralization method, maybe blood paparazzi, amino adsorption, IVIG spenactomy. This anti-vcell therapy that includes MMF, retoximab, IVIG spenactomy that can be used. Additionally anti-plasmous therapy using photosomate and anti-vcell therapy involving T cell depreting agent like ATG are the options. Conversion to techrolinose based regime and the use of terniminal complement pathway inhibitor maybe like acolyzoma are also viable treatment options. Now, let's discuss about the induction therapy using anti-d cell therapy for the kidney transplantation. So during kidney transplantation patients typically receive induction therapy that aims to suppress the T cell imposite including T cell imposite depreting agent such as hemoglobin or IL2 inhibitor. This therapies are result in an notable decrease in cellular rejection which is more common during the initial weeks or months following transplantation but can also occur later particularly when immunosuppression is reduced. Let us look at ATG as a promising induction therapy in kidney transplant. So hemoglobin has shown promising as an induction agent when combined with barata set in phase 2 trial where the low rejection rates were observed. Hemoglobin mediated T cell depletion is believed to increase the therapeutic efficacy of the transplant and transferred T rate by encountering reduced number of T cell imposite. According to a study biopsy-brewed acute rejection rates were lower in the hemoglobin group after the 1 year that is 15.6% versus 25.5% as depicted in the graph. Acute rejection with hemoglobin reduction was also less severe and the initial rate required anti-boreate treatment was significantly lower that is at 1.4% versus 8% afterward. In the US, hemoglobin is the most frequently used induction agent with antibody induction being used in the majoring for kidney transplantation and almost 50% of the thoracic organ transplantation. Let us look at the optimum clinical outcome of hemoglobin in kidney transplantation as an induction agent. We can see in the graph that hemoglobin results in the lower incidence of the acute restriction and improved patient's survival in kidney transplant receiving compared to the low-indexion therapy in two randomized prospective trials. Hemoglobin was well-colored and with minimal infection and low incidence of malignancy and is a polyglonal antibody preparation. It targets a wide range of surface molecules that are not only experienced T cells but also on the other leukocytes and thus potentially also deplete other effector leukocytes thereby possibly further promoting the bone marrow and graft. Now we will discuss the complement system inhibitor as novel therapeutic approach to avoid the graph rejection in kidney transplanting. With this new therapeutic strategy targeting the complement system and eliminating an element of signaling such as immunizing anti-C5 antibody on monocyte or denteratic cell of the inid immunosystem may be necessary to prevent antibody mediated rejection and achieve long-term tolerance in human aloelectric therapy. Intimiter of this complement system may be as complement antionines could prevent the acute pathological effect of complement activation such as blocking C5 and MSE formation thereby preventing the acute rejection. Potential area for therapy glues prevention of ABM antibody mediated endothelial cell injury through complement blockage and the depletion of the plasma cell, secreting donor specific antibody from the bone marrow using fruit T-A's room inhibitor. So the key message is immunophilogy should become a key squish area of nephrology in and understanding the role of immunosystem in kidney disease and defining the optimum immune-modulating treatment study. About 20-30% of acute rejection episodes involves numeral rejection with antinone and antifurne, circulating donor specific antibodies and C4D in the pterotibular capillary, other hallmark of ABM1. HLA applied mismention analysis improves the risk assessment of donor-reciput HLA incompatibility and helps to the prediction of kidney transplant outcome. HLA mismention is a critical prognostic factor that affects the graft and the recipient's survival. HLA DR mismention helps the substantial impact of the recipient's graft server. Hylomine has shown the promising and very important induction agent in combination with belladosip, thymoglobulin mediated T cell depletion is the considering the therapeutic efficacy of the transfer T-R
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