Immunosuppressive Toxicity Research Articles

An Updated Comprehensive Review on Diseases Associated with Nephrotic Syndromes.

There have been exciting advances in our knowledge of primary glomerular diseases and nephrotic syndromes in recent years. Beyond the histological pattern from renal biopsy, more precise phenotyping of the diseases and the use of modern nephrogenetics helps to improve treatment decisions and sometimes also avoid unnecessary exposure to potentially toxic immunosuppression. New biomarkers have led to easier and more accurate diagnoses and more targeted therapeutic decisions. The treatment landscape is becoming wider with a pipeline of promising new therapeutic agents with more sophisticated approaches. This review focuses on all aspects of entities that are associated with nephrotic syndromes with updated information on recent advances in each field. This includes podocytopathies (focal segmental glomerulosclerosis and minimal-change disease), membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, fibrillary glomerulonephritis, amyloidosis, and monoclonal gammopathy of renal significance in the context of the nephrotic syndrome, but also renal involvement in systemic diseases, diabetic nephropathy, and drugs that are associated with nephrotic syndromes.

Harnessing Immune Cell Metabolism to Modulate Alloresponse in Transplantation.

Immune cell metabolism plays a pivotal role in shaping and modulating immune responses. The metabolic state of immune cells influences their development, activation, differentiation, and overall function, impacting both innate and adaptive immunity. While glycolysis is crucial for activation and effector function of CD8 T cells, regulatory T cells mainly use oxidative phosphorylation and fatty acid oxidation, highlighting how different metabolic programs shape immune cells. Modification of cell metabolism may provide new therapeutic approaches to prevent rejection and avoid immunosuppressive toxicities. In particular, the distinct metabolic patterns of effector and suppressive cell subsets offer promising opportunities to target metabolic pathways that influence immune responses and graft outcomes. Herein, we review the main metabolic pathways used by immune cells, the techniques available to assay immune metabolism, and evidence supporting the possibility of shifting the immune response towards a tolerogenic profile by modifying energetic metabolism.

A novel cabazitaxel liposomes modified with ginsenoside Rk1 for cancer targeted therapy

Objective: In this study, we aim to enhance the anti-prostate cancer efficacy of cabazitaxel (CTX) and reduce its immunosuppression and systemic toxicity by developing CTX-loaded liposomes modified with ginsenoside Rk1 (Rk1/CTX-Lip). Methods: Physical and chemical properties of Rk1/CTX-Lip were investigated. We evaluated the biological functions of Rk1/CTX-Lip, both in vitro and in vivo. A subcutaneous prostate cancer (RM-1)-bearing mouse model was established to study the efficacy of Rk1/CTX-Lip inhibition in tumors. Simultaneously, a Candida albicans infection model was established in tumor-bearing mice to study the infection-relieving efficacy of Rk1/CTX-Lip. Finally, biocompatibility and in vivo safety of Rk1/CTX-Lip were evaluated. Results: We successfully prepared Rk1/CTX-Lip, achieving high CTX encapsulation efficiency (97.24 ± 0.75)% and physical stability. Rk1/CTX-Lip demonstrated evasion of macrophage phagocytosis, effective tumor tissue targeting, and a significant reduction (>50%) in average tumor volume compared with Chol/CTX-Lip. Moreover, it relieved the concurrent infection burden and effectively regulated immune organs and cells, demonstrating superior biocompatibility. Conclusion: Rk1/CTX-Lip presents a promising new therapy for prostate cancer and holds potential for relieving concurrent fungal infections in cancer patients with low immunity.

Low-dose Interleukin-2 Therapy: Fine-tuning Treg in Solid Organ Transplantation?

Regulatory T cells (Treg), a subset of CD4 + T cells, are potent regulators of immune reactions, which have been shown to be a promising therapeutic alternative to toxic immunosuppressive drugs. Data support the utility of Treg in managing immunopathologies, including solid organ transplant rejection, graft-versus-host disease, and autoimmune disorders. Notably, reports suggest that interleukin-2 (IL-2) is critical to survival of Treg, which constitutively express high levels of CD25, that is, the IL-2 receptor α-chain, and are exquisitely sensitive to IL-2, even at very low concentrations in contrast to effector T cells, which only upregulate IL-2 receptor α-chain on activation. This has led to the notion of using low doses of exogenous IL-2 therapeutically to modulate the immune system, specifically Treg numbers and function. Here, we summarize developments of clinical experience with low-dose IL-2 (LD-IL-2) as a therapeutic agent. So far, no clinical data are available to support the therapeutic use of LD-IL-2 therapy in the solid organ transplant setting. For the latter, fine-tuning by biotechnological approaches may be needed because of the narrow therapeutic window and off-target effects of LD-IL-2 therapy and so to realize the therapeutic potential of this molecule.

Efficacy and safety of guttiferone E in melanoma-bearing mice.

Melanoma, an aggressive and potentially fatal skin cancer, is constrained by immunosuppression, resistance, and high toxicity in its treatment. Consequently, there is an urgent need for innovative antineoplastic agents. Therefore, this study investigated the antimelanoma potential of guttiferone E (GE). In an allogeneic murine B16 melanoma model, GE was administered subcutaneously and intraperitoneally. Antitumor evaluation included tumor volume/weight measurements and histopathological and immunohistochemical analysis. Furthermore, the toxicity of the treatments was evaluated through body/organ weights, biochemical parameters, and genotoxicity. Subcutaneous administration of 20 mg/kg of GE resulted in a significant reduction in both tumor volume and weight, effectively suppressing melanoma cell proliferation as evidenced by a decrease in mitotic figures. The tumor growth inhibition rate was equivalent to 54%. This treatment upregulated cleaved caspase-3, indicating apoptosis induction. On the other hand, intraperitoneal administration of GE showed no antimelanoma effect. Remarkably, GE treatments exhibited no toxicity, evidenced by non-significant differences in body weight gain, as well as organ weight, biochemical parameters of nephrotoxicity and hepatotoxicity, and genotoxic damage. This study revealed, for the first time, the efficacy of subcutaneous administration of GE in reducing melanoma, in the absence of toxicity. Furthermore, it was observed that the apoptotic signaling pathway is involved in the antimelanoma property of GE. These findings offer valuable insights for further exploring GE's therapeutic applications in melanoma treatment.

Enhancing antitumor immunity with stimulus-responsive mesoporous silicon in combination with chemotherapy and photothermal therapy.

Due to the immunosuppressive tumor microenvironment (TME) and potential systemic toxicity, chemotherapy often fails to elicit satisfactory anti-tumor responses, so how to activate anti-tumor immunity to improve the therapeutic efficacy remains a challenging problem. Photothermal therapy (PTT) serves as a promising approach to activate anti-tumor immunity by inducing the release of tumor neoantigens in situ. In this study, we designed tetrasulfide bonded mesoporous silicon nanoparticles (MSNs) loaded with the traditional drug doxorubicin (DOX) inside and modified their outer layer with polydopamine (DOX/MSN-4S@PDA) for comprehensive anti-tumor studies in vivo and in vitro. The MSN core contains GSH-sensitive tetrasulfide bonds that enhance DOX release while generating hydrogen sulfide (H2S) to improve the therapeutic efficacy of DOX. The polydopamine (PDA) coating confers acid sensitivity and mild photothermal properties upon exposure to near-infrared (NIR) light, while the addition of hyaluronic acid (HA) to the outermost layer enables targeted delivery to CD44-expressing tumor cells, thereby enhancing drug accumulation at the tumor site and reducing toxic side effects. Our studies demonstrate that DOX/MSN@PDA-HA can reverse the immunosuppressive tumor microenvironment in vivo, inducing potent immunogenic cell death (ICD) of tumor cells and improving anti-tumor efficacy. In addition, DOX/MSN@PDA-HA significantly suppresses tumor metastasis to the lung and liver. In summary, DOX/MSN@PDA-HA exhibits controlled drug release, excellent biocompatibility, and remarkable tumor inhibition capabilities through synergistic chemical/photothermal combined therapy.

Cutting edge of immune response and immunosuppressants in allogeneic and xenogeneic islet transplantation.

As an effective treatment for diabetes, islet transplantation has garnered significant attention and research in recent years. However, immune rejection and the toxicity of immunosuppressive drugs remain critical factors influencing the success of islet transplantation. While immunosuppressants are essential in reducing immune rejection reactions and can significantly improve the survival rate of islet transplants, improper use of these drugs can markedly increase mortality rates following transplantation. Additionally, the current availability of islet organ donations fails to meet the demand for organ transplants, making xenotransplantation a crucial method for addressing organ shortages. This review will cover the following three aspects: 1) the immune responses occurring during allogeneic islet transplantation, including three stages: inflammation and IBMIR, allogeneic immune response, and autoimmune recurrence; 2) commonly used immunosuppressants in allogeneic islet transplantation, including calcineurin inhibitors (Cyclosporine A, Tacrolimus), mycophenolate mofetil, glucocorticoids, and Bortezomib; and 3) early and late immune responses in xenogeneic islet transplantation and the immune effects of triple therapy (ECDI-fixed donor spleen cells (ECDI-SP) + anti-CD20 + Sirolimus) on xenotransplantation.

Aflatoxin B1 impairs porcine oocyte quality via disturbing intracellular membrane system and ATP production

Aflatoxin is the most common type of mycotoxins in contaminated corn, peanuts and rice, which affects the livestock and ultimately endangers human health. Aflatoxin is reported to have carcinogenicity, mutation, growth retardation, immunosuppression and reproductive toxicity. In present study we reported the causes for the declined porcine oocyte quality under aflatoxin exposure. We set up an in vitro exposure model and showed that aflatoxin B1 disturbed cumulus cell expansion and oocyte polar body extrusion. We found that aflatoxin B1 exposure disrupted ER distribution and elevated the expression of GRP78, indicating the occurrence of ER stress, and the increased calcium storage also confirmed this. Besides, the structure of cis-Golgi apparatus, another intracellular membrane system was also affected, showing with decreased GM130 expression. The oocytes under aflatoxin B1 exposure showed aberrant lysosome accumulation and higher LAMP2 expression, a marker for lysosome membrane protection, and this might be due to the aberrant mitochondria function with low ATP production and the increase of apoptosis, since we found that BAX expression increased, and ribosomal protein which is also an apoptosis-related factor RPS3 decreased. Taken together, our study revealed that aflatoxin B1 impairs intracellular membrane system ER, Golgi apparatus, lysosome and mitochondria function to affect porcine oocyte maturation quality.

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)

Utilizing chemotherapy-induced tumor RNA nanoparticles to improve cancer chemoimmunotherapy.

Chemotherapy has become a popular combination strategy to improve the response rate of immunotherapy since certain chemotherapeutic drugs kill tumor cells by an immunogenic cell death (ICD) pathway, which activates antitumor immune responses. Unfortunately, the synergistic effect of chemoimmunotherapy can be impaired due to the toxicities of chemotherapeutic agent-induced lymphatic depletion and immunosuppression. In this study, we present an approach to improve immunotherapy by using tumor RNA nanoparticles (RNA-NPs) where RNA is directly extracted from chemotherapy-treated cancer cells and then condensed by protamine via electrostatic interactions to form complexes. Such RNA-NPs can be effectively taken up by dendritic cells (DCs) in the draining lymph nodes after subcutaneous injection. Compared with noninduced tumor RNA nanoparticles (N-RNA-NPs), chemotherapy-induced tumor RNA nanoparticles (C-RNA-NPs) can significantly promote DC maturation and stimulate a stronger immune response against established CT-26 colon carcinoma. Besides, C-RNA-NPs can improve the efficacy of immune checkpoint blockade (ICB) therapy by facilitating the infiltration of intratumoral T cells and increasing the ratio of CD8+ T cells to regulatory T cells (Tregs). More importantly, the synergistic effect of chemoimmunotherapy is also enhanced by treatment with C-RNA-NPs. STATEMENT OF SIGNIFICANCE: Although immune checkpoint blockade therapy has been demonstrated to be effective in some advanced cancers, the low response rate has significantly limited its clinical application. To address this issue, a new strategy for improving cancer immunotherapy using chemotherapy-induced tumor RNA nanoparticles (C-RNA-NPs) is developed in this work. The proposed C-RNA-NPs could be captured by dendritic cells, which were then stimulated to the maturation status to initiate an anticancer immune response. Furthermore, the response rate to immunotherapy was significantly increased by promoting intratumoral T-cell infiltration and elevating the intratumoral ratio of CD8+ T cells to regulatory T cells after treatment with C-RNA-NPs. Therefore, C-RNA-NPs have the potential to improve cancer immunotherapy.

Exploring Local Immune Modulation With Rapamycin-eluting Micelles to Preserve Islet Graft Function in Mice

Islet transplantation is an effective means for a subset of people with type 1 diabetes to achieve insulin independence; however, lifelong systemic immunosuppression required to subvert the immune response remains a major barrier in patient inclusion. Herein, we explore the use of a localized drug delivery system to preserve islet allograft function, reducing the need for toxic systemic immunosuppression. Rapamycin (rapa), an immunosuppressant used in clinical islet transplantation, was encapsulated in Food and Drug Administration-approved poly(lactide-co-glycolide) (PLGA) micelles.

Accommodation in allogeneic and xenogeneic organ transplantation: Prevalence, impact, and implications for monitoring and for therapeutics

Accommodation refers to acquired resistance of organs or tissues to immune or inflammatory reactions that might otherwise cause severe injury or rejection. As first observed in ABO-incompatible kidney transplants and heterotopic cardiac xenografts, accommodation was identified when organ transplants continued to function despite the presence of anti-graft antibodies and/or other reactants in the blood of recipients. Recent evidence suggests many and perhaps most organ transplants have accommodation, as most recipients mount B cell responses specific for the graft. Wide interest in the impact of graft-specific antibodies on the outcomes of transplants prompts questions about which mechanisms confer protection against such antibodies, how accommodation might be detected and whether and how rejection could be superimposed on accommodation. Xenotransplantation offers a unique opportunity to address these questions because immune responses to xenografts are easily detected and the pathogenic impact of immune responses is so severe. Xenotransplantation also provides a compelling need to apply these and other insights to decrease the intensity and toxicity of immunosuppression that otherwise could limit clinical application.

242.7: Influence of CYP3A5 Polymorphisms on Tacrolimus Dosing in Renal Transplant Recipients

Introduction: Tacrolimus is a commonly used immunosuppressant after kidney transplantation it has narrow theraupetic range and demonstrates wide interindividual variability in pharmacokinetics leading to potential under immunosuppression or tacrolimus toxicity genetic polymorphism in CYP3A5 enzyme expression contributes to differences in tacrolimus bioavailibility between individuals. Aim of the study: Ti evaluate pharmacogenomic effect of CYP3A5 gene polymorphisms on tacrolimus dosing in renal transplant recipients. Materials and Methods: Present study we investigated pharmacogenomics associations of common CYP3A5 polymorphisms with requirements of tacrolimus in renal transplant patients: □INCLUSION CRITERIA - 50 patients on tacrolimus based triple immunosuppression were genotyped for cyp3A5 polymorphism most allels- *1/*1,*1/*3,*3/*3 alleles. □EXCLUSION CRITERIA- those patients on CYP inducers or inhibitors were excluded demographic data, weight based tacrolimus doses, serum tacrolimus level at 1 month, 3 months 1 year and present tacrolimus trough level were collected. Data was statistically analysed. Results: Mean age of the recipients was 33.41+/-10.2,72% were males mean tacrolimus level at 1 month was 8ng/ml (7-10ng/ml) at 1 month post transplant cyp *1/*1 was 5.75+_0.95,tac level in cyp3a5 *1/*3 was 9.52∔_1.42,CYP3A5*3/*3 -10.26+_1.02 with significant P VALUE <0.01 among patients with high tac level 36% were poor metabolisers,50% intermediate metabolizers,none of the extensive metabolisers had higher tacrolimus level. At>3 months of transplantation tac level in cyp3a5 *1/*1 was 5.75∔0.95, cyp3a5 *1/*3 was 6.33∓1.17, cyp3a5 *3/*3 was 6.78∔-0.8 with significant P value < 0.01. 56% developed tac toxicity - 84%(*3/*3) poor metabolisers, 14.3% in intermediate *1/*3 metabolisers.125 developed rejections in first three months of transplant,90.755 were extensive metabolisers Discussion: Tacrolimus toxicity as well as rejection due to sub theraupetic levels influence graft outcomes. bioavailibility of tacrolimus varies widely due to gene polymorphisms of CYP3A5 gene. CYP3A5*1/*1 had lower tac level in blood resulting higher rates of rejection requiring 1.5 to 2 times higher dose compared to poor metabolisersand intermediate metabolizers. Poor metabolizers *3/*3 had tacrolimus related toxicity at similar dose adjusted tac levels, indicating lower dose for maintanence (0.06mg/kg). Conclusion: Genotyped based dosing may improve achievement of theraupetic drug concentrations with reduced drug related complications in the era of personalised medicine.

Manipulating adrenergic stress receptor signalling to enhance immunosuppression and prolong survival of vascularized composite tissue transplants.

BackgroundVascularized composite tissue allotransplantation (VCA) to replace limbs or faces damaged beyond repair is now possible. The resulting clear benefit to quality of life is a compelling reason to attempt this complex procedure. Unfortunately, the high doses of immunosuppressive drugs required to protect this type of allograft result in significant morbidity and mortality giving rise to ethical concerns about performing this surgery in patients with non‐life‐threatening conditions. Here we tested whether we could suppress anti‐graft immune activity by using a safe β2‐adrenergic receptor (AR) agonist, terbutaline, to mimic the natural immune suppression generated by nervous system‐induced signalling through AR.MethodsA heterotopic hind limb transplantation model was used with C57BL/6 (H‐2b) as recipients and BALB/c (H‐2d) mice as donors. To test the modulation of the immune response, graft survival was investigated after daily intraperitoneal injection of β2‐AR agonist with and without tacrolimus. Analyses of immune compositions and quantification of pro‐inflammatory cytokines were performed to gauge functional immunomodulation. The contributions to allograft survival of β2‐AR signalling in donor and recipient tissue were investigated with β2‐AR−/− strains.ResultsTreatment with the β2‐AR agonist delayed VCA rejection, even with a subtherapeutic dose of tacrolimus. β2‐AR agonist decreased T‐cell infiltration into the transplanted grafts and decreased memory T‐cell populations in recipient's circulation. In addition, decreased levels of inflammatory cytokines (IFN‐γ, IL‐6, TNF‐α, CXCL‐1/10 and CCL3/4/5/7) were detected following β2‐AR agonist treatment, and there was a decreased expression of ICAM‐1 and vascular cell adhesion molecule‐1 in donor stromal cells.Conclusionsβ2‐AR agonist can be used safely to mimic the natural suppression of immune responses, which occurs during adrenergic stress‐signalling and thereby can be used in combination regimens to reduce the dose needed of toxic immunosuppressive drugs such as tacrolimus. This strategy can be further evaluated for feasibility in the clinic.

Glyphosate-induced liver and kidney dysfunction, oxidative stress, immunosuppression in Nile tilapia, but ginger showed a protection role

The water-borne herbicides are involved in the toxicity of aquatic animals resulting in impaired health status and low productivity. Dietary medicinal herbs present a practical solution to relieve the impacts of herbicides toxicity on the performances of aquatic animals. Herein, we investigated the toxicity of commercial glyphosate-induced oxidative stress, immunosuppression, liver and kidney dysfunction, and the protective role of ginger or ginger nanoparticles in Nile tilapia. Fish were allocated into four groups: the first group presented the control without glyphosate toxicity and ginger feeding, the second group intoxicated with glyphosate at 0.6 mg/L and fed ginger free diet, the third group intoxicated with glyphosate and fed ginger at 2.5 g/kg, and the fourth group intoxicated with glyphosate and fed ginger nanoparticles at 2.5 g/kg. Fish were kept under the experimental conditions for four weeks, and the samples of blood and tissues were collected after 2 and 4 weeks. Markedly, fish exposed to glyphosate showed the highest ALT and AST activities, glucose and cortisol levels, and malondialdehyde levels (MDA) in gills and tissues. While fish in the control and fish intoxicated with glyphosate and fed ginger nanoparticles had the lowest ALT and AST activities, glucose and cortisol levels, and MDA levels after 2 and 4 weeks (P < 0.05). Fish fed dietary ginger had lower ALT and AST activities, glucose and cortisol levels, and MDA levels than the glyphosate intoxicated group after 2 and 4 weeks (P < 0.05). Interestingly, fish-fed ginger nanoparticles showed lower urea and creatinine levels and higher total protein, albumin, and globulin than the glyphosate intoxicated group (P < 0.05) and similar to the control (P > 0.05). Further, fish intoxicated with glyphosate and fed ginger nanoparticles had the highest GSH, lysozyme activity, and immunoglobulin levels after 2 and 4 weeks (P < 0.05). In conclusion, ginger nanoparticles are superior to the standard ginger form in enhancing the antioxidative and immune responses of Nile tilapia exposed to glyphosate.

Exploring e-psychonauts perspectives towards cocaine effects and toxicity

BackgroundAccording to the World Drug Report, cocaine is the second most used drug globally after cannabis. Online discussion forums enable the understanding of authentic drug users’ experience as it is anonymous. Therefore, this study determined the uses, effects and toxicity of cocaine from the perspectives’ of e-psychonauts.MethodsA qualitative study was conducted using six popular discussion forums. From these discussion forums, 1229 posts from 50 threads were subject to thematic analysis. Hence, the information from these threads were examined carefully for patterns and codes among the data. The codes were then collated into subthemes and themes.ResultsThe four main themes emerging from the study were related to cocaine characteristics and use, e-psychonauts’ knowledge and experience, desired effects and adverse events. The main characteristic associated with cocaine use was purity that was highest in the US being nearest to the source. The most common cutting agent encountered in cocaine samples was levamisole that increased the chances of immunosuppression and cardiovascular toxicity. Purity depended on the source of purchase that included street dealers, dark web and surface web. Hence, e-psychonauts recommended purchase of cocaine from known dealers rather than websites with unknown sources. E-psychonauts mainly used cocaine in social context and parties or to self-medicate against anxiety and depression. Effects desired from cocaine use were mainly euphoria and increased energy. However, tachycardia and myocardial infarction were the main adverse events. It is noteworthy to mention that myocardial infarction was idiosyncratic and was often lethal. Myocardial infarction was more often reported when cocaine was combined with alcohol due to the production of cocaethylene. Social harm was also reported as a consequence for the use of cocaine that resulted in homelessness and broken relationships.ConclusionOnline discussion forums allowed the understanding of e-psychonauts’ experience with cocaine use. Not only it informed about the sources and modalities of use of cocaine but also about the adverse events and social harm associated with cocaine use. The present findings serve as useful information for practitioners and healthcare professionals dealing with cocaine users.

The trend for transplant medicine development: induction of immune tolerance or regulation of immune response?

One of the greatest medical advances of the last century has been the introduction of organ transplantation. However, despite the considerable potential of transplantation as often the only therapy for severe diseases, the toxicity of immunosuppressive drugs supporting the transplant remains a serious problem for its further development. Modification of immune response in order to form tolerance to the transplanted organ can play an important role on the way to minimize immunosuppression. Successful cases of withdrawal of immunosuppressive drugs for medical reasons in kidney and liver transplantation recorded in the literature, as well as the results obtained in the process of modeling such a situation in the experiment, prove that achieving tolerance in organ transplantation is fundamentally possible.The aim of this review is to investigate the ways of immunologic suppression and fundamental mechanisms of immunologic tolerance in the field of transplantation and to review the latest clinical achievements in this respect.The review describes various approaches to the induction of central tolerance in solid organ transplantation implemented in the framework of the original clinical protocols. Special attention is given to a new direction in transplantation medicine – cell technologies providing tolerogenic effect by means of peripheral mechanisms activation, in particular due to activation of suppressor function of regulatory T cells.We draw the attention to the advantages and disadvantages of these two trends. Which of them is preferable? In which direction will scientific thought be developed for realization of the long-term goal of transplantologists: to avoid allograft rejection without affecting the physiological homeostasis of the body? Possible answers to these questions are discussed in this review.

MO485: Chronic Kidney Disease in Patients With Lung Transplant

Abstract BACKGROUND AND AIMS The incidence of chronic kidney disease (CKD) in patients with lung transplantation (LTx) has increased over the last decades. Progression factors recognized in the development of CKD are: older age and comorbidity of recipients, immunosuppressive (IS) toxicity and longer survival. There is a lack of specific information about other risk factors or specific preventive management of CKD. METHOD Retrospective, single-centre study including all patients with LTx on Nephrology outpatient clinic among 2007 and 2020. Demographic, comorbidity and intercurrent events, renal function impairment, proteinuria and IS treatment were analyzed. We defined composite renal event (MARE) as renal replacement therapy (RRT), death or doubling serum creatinine. RESULTS A total of 69 LTx receptors (79.4% double LTx) were followed in a dedicated outpatient nephrology clinic. A total of 52.2% male, mean age at LTx 48.3 years (SD 16.6). Etiology of lung disease: cystic fibrosis (30.4%), obstructive lung disease or emphysema (33.3%) and interstitial disease (30.4%). After LTx, as complications, infection was the most frequent event (89.7%) and 49.3% presented neoplasic illness. The mean time from LTx until first nephrologist evaluation was 6.6 years (2 months–19.9 years) and main comorbidities were: hypertension (81.2%), diabetes mellitus (52.2%), dyslipidemia (50.7%), 60.3% former smokers and 26.1% had suffer from a previous CV event. After 1 year of LTx, mean eGFR decreased to 49.8 mL/min, which means that only in the first year after LTx there is a loss of ∼50% of mean kidney function. Factor associated with impaired kidney function at the first year after LTxw was cystic fibrosis (higher percentage in the rapid progression group). At first evaluation by Nephrology, the mean eGFR was 30.9 mL/min (SD 15.3), with a CKD distribution: 39.4% CKD 3; 45.5% CKD 4 and 12.1% CKD 5 (&amp;lt;15). Clinical study and biopsy define CKD etiologies: CNI toxicity (68.1%) thrombotic microangiopathy (11.6%), tubular (10.1%), vascular (7.3%) and glomerulopathies (2.9%). A total of 88.4% patients reached MARE at the end of the study. A total of 24 patients required RRT (mean time since LTx 9.2 years) and thereafter, 10 received a kidney transplantation (KTx). In Dyalisis group, a higher mortality was observed versus no dialysis group (24 versus 2.2%), a higher percentage of vascular origin disease with a further deterioration of eGFR at the time of referral to Nephrology. At the end of follow-up, 15 patients died (14 were in RRT), 5 continued on HD and 5 with a functional KTx, and 44 patients were still without RRT. CONCLUSION

Seeking the Sertoli cell complement inhibitory signature to prolong transplant survival

Abstract Clinical transplantation can treat various illnesses, although without the use of toxic immunosuppressants transplanted tissue is rejected by the immune system. Complement, an enzymatic cascade that leads to cytolysis by insertion of the membrane attack complex (MAC), is a significant component in transplant rejection. Interestingly, Sertoli cells (SC) survive long-term after transplantation across immune barriers without immunosuppression. This study used allotransplant (between same species) and xenotransplant (between different species) models to investigate the role of complement inhibition in SC extended survival. Since SC were resistant to in vitro complement killing, mouse or pig SC were transplanted into mice or rats, respectively. Grafts were collected and analyzed for MAC. MAC was not detected on SC transplants, indicating that SC inhibit complement before MAC deposition, possibly through expression of complement inhibitory proteins (CIP). Bioinformatic analyses of mouse or pig SC identified expression of 13 CIP. After expression of two key CIP, CD46 and CD55, were knocked down, SC were killed by complement in vitro. Taken together, these data indicate that the SC complement inhibitory signature is critical for SC graft survival. Understanding SC complement inhibition is important as it could lead to improved transplant survival with a decreased requirement of harsh immunosuppressants, making this procedure more attainable for patients. Supported by grants from the CH foundation, the South Plains Foundation, and the Mary Lou Clements-Mann Scholarship

POS-774 Role of Noro virus infection in post renal transplant persistent diarrhea

Diarrhea is common gastrointestinal problem in kidney transplant recipients. Numerous cases of post-transplant diarrhea in the past have been ascribed solely to the toxicity of immunosuppressive drugs, leading to diagnostic misconceptions. Noro Virus, one of the common cause of acute diarrhea in adult is emerging as important cause of persistent diarrhea in solid organ transplant recipients.Here, we are presenting our experience with chronic Noro virus infection in renal transplant recipients.