Organ Transplant Rejection Research Articles

In Silico Analysis: HLA-DRB1 Gene’s Variants and Their Clinical Impact

The HLA-DRB1 gene encodes a protein that is essential for the immune system. This gene is important in organ transplant rejection and acceptance, as well as multiple sclerosis, systemic lupus erythematosus, Addison’s disease, rheumatoid arthritis, caries susceptibility, and Aspirin-exacerbated respiratory disease. The following Homo sapiens variants were investigated: single-nucleotide variants (SNVs), multi-nucleotide variants (MNVs), and small insertions–deletions (Indels) in the HLA-DRB1 gene via coding and untranslated regions. The current study sought to identify functional variants that could affect gene expression and protein product function/structure. ALL target variants available until April 14, 2022, were obtained from the Single Nucleotide Polymorphism database (dbSNP). Out of all the variants in the coding region, 91 nsSNVs were considered highly deleterious by seven prediction tools and instability index; 25 of them are evolutionary conserved and located in domain regions. Furthermore, 31 indels were predicted as harmful, potentially affecting a few amino acids or even the entire protein. Last, within the coding sequence (CDS), 23 stop-gain variants (SNVs/indels) were predicted as high impact. High impact refers to the assumption that the variant will have a significant (disruptive) effect on the protein, likely leading to protein truncation or loss of function. For untranslated regions, functional 55 single-nucleotide polymorphisms (SNPs), and 16 indels located within microRNA binding sites, furthermore, 10 functionally verified SNPs were predicted at transcription factor-binding sites. The findings demonstrate that employing in silico methods in biomedical research is extremely successful and has a major influence on the capacity to identify the source of genetic variation in diverse disorders. In conclusion, these previously functional identified variants could lead to gene alteration, which may directly or indirectly contribute to the occurrence of many diseases. The study’s results could be an important guide in the research of potential diagnostic and therapeutic interventions that require experimental mutational validation and large-scale clinical trials.

Питейные заведения в романе «Преступление и наказание». Художественная деталь в правовом поле питейной реформы 1861 года

By the middle of the 19th century, the theme of drunkenness as the cause of the most heinous vices and crimes had become one of the most discussed. Numerous abuses by the owners of drinking establishments led to a spontaneous manifestation of people’s sobriety in the late 50s of the 19th century. This caused significant damage to the state budget. The result of this confrontation was the introduction of a new government policy on drink sales. The terminological replacement of “kabak” with drinking house gradually replaced this name from everyday language but retained its historically negative reputation in the public mind. By the middle of the 19th century, the use of the lexeme “kabak” in the literary language already had a distinct metaphorical meaning. The “kabak”, as the main culprit of drunkenness and depravity, became the embodiment of social evil, and the problem of drunkenness was realized as a religious opposition “righteousness — sin.” The action of the novel Crime and Punishment takes place in the period of the first consequences of the new drinking reform. One of the features of the novel is Dostoevsky’s use of the lexeme “raspivochnaia” as an everyday colloquial name for a drinking house, carrying a pronounced emotional reaction of social rejection. “Raspivochnaia” is a thorough leitmotif of the story. It is an element of the general negative atmosphere of the city along with stuffiness, the smell of dust, lime, and slop. It is associated with descriptions of the psychological state of Raskolnikov. The mention of it accompanies all significant events and meetings for the characters. But the most important thing is its connection with the religious and moral problems of choice, with the inevitability of the fall into sin or the possibility of resurrection. This emotional and semantic image, which determines the further narrative, is built by Dostoevsky already at the very beginning of the novel, in the tavern where Marmeladov and Raskolnikov meet.

Chronic pain and the social context

The chronic pain complaint is still poorly accepted in the community and even sometimes in the health care system. It may trigger reactions of disbelief, suspicion or rejection. The legitimization and validation of the patient's suffering is a priority in order for him/her to feel believed and understood and improve his/her commitment to the treatment proposal. The social consequences of chronic pain include various limitations, a reduction of activities, of personal and professional ties leading to social exclusion amplifying the painful experience. Exploring his/her social context during the consultation often helps the patient to re-establish significant links. It leads to wider therapeutic approaches focusing on the strengthening of social support, with documented benefits on pain experience, mood and quality of life.

Sestrinske intervencije pri aplikaciji oralnih preparata ciklosporina

Cyclosporine or cyclosporine A is an immunosuppressive medicine used after solid organ transplantation -heart, lungs, liver, pancreas, kidney and bone marrow - to prevent organ transplant rejection and to ensure proper functioning of the transplanted organ or bone marrow. It is used in the treatment of a wide range of autoimmune diseases in various branches of medicine -hematology, ophthalmology, dermatology, nephrology, rheumatology and gastroenterology. The discovery of cyclosporine and decades of its use have led to a revolution in transplant medicine. It can be administered intravenously, orally -capsules and oral solutions, intraocularly and by inhalation. Given the successful administration of cyclosporine is the most important factor in effectual therapeutic effect, the nurse must successfully perform all the stages of the administration of oral forms of this drug, which are: medicine storage, preparation for medicine administration, medicine administration, waste disposal and providing education of the patient and family members. During the performance of all these stages, ac-cording to the health care protocol, the nurse must demonstrate dexterity, skill, confidence and a professional attitude towards the patient, while respecting all ethical principles. A successful administration of cyclosporine requires a team approach involving the doctor, nurse, patient and family members, continual professional training, keeping pace with innovations in this field and constant work on improving communication skills.

How can marine invertebrates help prevent organ transplant rejection?

How can marine invertebrates help prevent organ transplant rejection?

Perbedaan Hasil Derajat Aglutinasi Serum Grouping Tube Test Dengan Suspensi Reagen NaCl 0,9% Siap Pakai dan Suspensi Reagen NaCl 0,9% Dari Garam Dapur

ABO blood group examination is a simple laboratory test performed to determine a person’s blood group. There are two types of ABO blood group test, namely cell grouping and serum grouping. Serum grouping examination is very important to prevent incompatible transfusion reactions and organ transplant rejection. Serum grouping was carried out using 10% saline wash suspension of cell A, B and O. The blood cell washing stage was used to remove fragile cells and interfering substances that could result in errors in the examination. The main ingredient used in the blood cell washing procedur is 0.9% NaCl. This study aims to determine the degree of agglutination serum grouping tube test with ready to use 0.9% NaCl reagent suspension and 0.9% NaCl reagent suspension from table salt. The type of research is an experiment. The study was conducted at UDD PMI South Sumatra Province on 30 December 2021 to 5 January 2022 with a totalsample of 67 samples. The results showed that the average degree of agglutination the serum grouping tube test with 0.9% NaCl reagent ready to use was 3.73 and the average degree of agglutination the serum grouping tube test with0.9% NaCl reagent from table salt was 3.69. Wilcoxon test results obtained p value = 0.450. The conclusion of the study, that there is no differences in the results of the agglutination serum grouping tube test with ready to use 0.9% NaCl reagen suspension and 0.9% NaCl reagent suspension from table salt. The table salt showed that 0.9% NaCl reagent can be used as alternative reagent NaCl 0.9% ready to use in the examination of Iserum grouping tube test.

Tissue-Targeted Drug Delivery Strategies to Promote Antigen-Specific Immune Tolerance.

During autoimmunity or organ transplant rejection, the immune system attacks host or transplanted tissue, causing debilitating inflammation for millions of patients. There is no cure for most of these diseases. Further, available therapies modulate inflammation through nonspecific pathways, reducing symptoms but also compromising patients' ability to mount healthy immune responses. Recent preclinical advances to regulate immune dysfunction with vaccine-like antigen specificity reveal exciting opportunities to address the root cause of autoimmune diseases and transplant rejection. Several of these therapies are currently undergoing clinical trials, underscoring the promise of antigen-specific tolerance. Achieving antigen-specific tolerance requires precision and often combinatorial delivery of antigen, cytokines, small molecule drugs, and other immunomodulators. This can be facilitated by biomaterial technologies, which can be engineered to orient and display immunological cues, protect against degradation, and selectively deliver signals to specific tissues or cell populations. In this review, some key immune cell populations involved in autoimmunity and healthy immune tolerance are described. Opportunities for drug delivery to immunological organs are discussed, where specialized tissue-resident immune cells can be programmed to respond in unique ways toward antigens. Finally, cell- and biomaterial-based therapies to induce antigen-specific immune tolerance that are currently undergoing clinical trials are highlighted.

Development And Optimisation Of Magnesium Alumino Metasilicate Loaded Tacrolimus Extended Release Tablets By Qbd Approach For Management Of Oragan Transplantation

The current present study was planned to formulate tacrolimus extended-release tablets to enhance drug activity. Tacrolimus is a calcineurin inhibitor used to treat mild to moderate atopic dermatitis and preclude organ transplant rejection. However, tacrolimus consists of low bioavailability and shorter half-life. Therefore, it was intended to formulate an extended release formulation with suitable polymers to upregulates its therapeutic response.The melt granulation method was used for the preparation of tacrolimus extended release tablets. The central composite design was employed for optimization at two level three factors. Crucial materials properties were the concentration of glyceryl behenate (X1), the concentration of Hypromellose (X2), and the concentration of PEG 6000 (X3).ANOVA has been implemented to interpret the data and design space.The tacrolimus extended release tablet was successfully formulated using melt granulation method and invitro profile of optimized batch compared with marketed formulation. The outcome of the study revealed that optimized formulation of tacrolimus shows 100% release at 12 h. Whereas, marketed formulation (Envarsus XR) also shows 100% release at12 h. Thus, the findings revealed that the optimized formulation was successfully prepared and suitable for extended release nature

Local and Systemic Injections of Human Cord Blood Myeloid-Derived Suppressor Cells to Prevent Graft Rejection in Corneal Transplantation.

Myeloid-derived suppressor cells (MDSCs) are therapeutic agents to prevent graft rejection in organ transplants by modulating inflammation. Herein, the immunosuppressive effect of human cord blood MDSCs on corneal allograft models was confirmed. CB-MDSCs were locally (subconjuctival, 5 × 105) or systemically (intravenous, 1 × 106) injected twice on days 0 and 7. A corneal transplantation model was established using C57BL/6 and BALB/c mice, and corneal graft opacity was measured to evaluate graft rejection up to 6 weeks. Results showed that graft survival in the MDSCs groups increased compared to vehicle groups after 42 days. Systemic and local MDSC administration inhibited the maturation (MHC-IIhi CD11c+) of dendritic cells (DCs) and the differentiation of interferon γ+ CD4+ Th1 in draining lymph nodes (LNs). However, vehicle groups increased the infiltration of CD3+ T cells and F4/80+ macrophages and produced prominent neovascular and lymphatic vessels into the graft site with increased mRNA expression of VEGF-A/C and VEGFR-1/R-3. Local MDSCs administration showed prominent anti-angiogenic/anti-lymphangiogenic effects even at lower MDSCs doses. Thus, CB-MDSCs could relatively suppress the infiltration of pathological T cells/macrophages into the corneas and the migration of mature DCs into draining LNs Therefore, ocular and systemic MDSCs administration showed therapeutic potential for preventing corneal allograft rejection.

IMPDH inhibition activates TLR-VCAM1 pathway and suppresses the development of MLL-fusion leukemia.

Inosine monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme in de novo guanine nucleotide synthesis pathway. Although IMPDH inhibitors are widely used as effective immunosuppressants, their antitumor effects have not been proven in the clinical setting. Here, we found that acute myeloid leukemias (AMLs) with MLL-fusions are susceptible to IMPDH inhibitors invitro. We also showed that alternate-day administration of IMPDH inhibitors suppressed the development of MLL-AF9-driven AML invivo without having a devastating effect on immune function. Mechanistically, IMPDH inhibition induced overactivation of Toll-like receptor (TLR)-TRAF6-NF-κB signaling and upregulation of an adhesion molecule VCAM1, which contribute to the antileukemia effect of IMPDH inhibitors. Consequently, combined treatment with IMPDH inhibitors and the TLR1/2 agonist effectively inhibited the development of MLL-fusion AML. These findings provide a rational basis for clinical testing of IMPDH inhibitors against MLL-fusion AMLs and potentially other aggressive tumors with active TLR signaling.

Therapeutic Antibodies in Cancer Treatment in the UK

The growing understanding of the molecular mechanisms of carcinogenesis accelerated the development of monoclonal therapeutic antibodies to specifically target multiple cancer pathways. Recombinant protein therapeutics now constitute a large proportion of yearly approved medicines. Oncology, autoimmune diseases and to a smaller degree the prophylaxis of organ transplant rejection are their main application areas. As of the date of this review, 37 monoclonal antibody products are approved for use in cancer treatments in the United Kingdom. Currently, the antibody therapeutics market is dominated by monoclonal immunoglobulins (IgGs). New types of recombinant antibody therapeutics developed more recently include bispecific recombinant antibodies and other recombinantly produced functional proteins. This review focuses on the approved therapeutic antibodies used in cancer treatment in the UK today and describes their antigen targets and molecular mechanisms involved. We provide convenient links to the relevant databases and other relevant resources for all antigens and antibodies mentioned. This review provides a comprehensive summary of the different monoclonal antibodies that are currently in clinical use primarily in malignancy, including their function, which is of importance to those in the medical field and allied specialties.

Natural Compound 2,2′,4′-Trihydroxychalcone Suppresses T Helper 17 Cell Differentiation and Disease Progression by Inhibiting Retinoid-Related Orphan Receptor Gamma T

Retinoid-related orphan receptor γt (RORγt), a vital transcription factor for the differentiation of the pro-inflammatory Th17 cells, is essential to the inflammatory response and pathological process mediated by Th17 cells. Pharmacological inhibition of the nuclear receptor RORγt provides novel immunomodulators for treating Th17-driven autoimmune diseases and organ transplant rejection. Here, we identified 2,2',4'-trihydroxychalcone (TDC), a natural chalcone derivant, binds directly to the ligand binding domain (LBD) of RORγt and inhibited its transcriptional activation activity. Using three mice models of Th17-related diseases, it was found that the administration of TDC effectively alleviated the disease development of experimental autoimmune encephalomyelitis (EAE), experimental colitis, and skin allograft rejection. Collectively, these results demonstrated TDC targeting RORγt to suppress Th17 cell polarization, as well as its activity, thus, indicating the potential of this compound in treating of Th17-related autoimmune disorders and organ transplant rejection disorders.

Influence of the Photodegradation of Azathioprine on DNA and Cells.

Azathioprine (AZA) is a pharmacologic immunosuppressive agent administrated in various conditions such as autoimmune disease or to prevent the rejection of organ transplantation. The mechanism of action is based on its biologically active metabolite 6-mercaptopurine (6-MP), which is converted, among others, into thioguanine nucleotides capable of incorporating into replicating DNA, which may act as a strong UV chromophore and trigger DNA oxidation. The interaction between azathioprine and DNA, before and after exposure to solar simulator radiation, was investigated using UV-vis spectrometry and differential pulse voltammetry at a glassy carbon electrode. The results indicated that the interaction of AZA with UV radiation was pH-dependent and occurred with the formation of several metabolites, which induced oxidative damage in DNA, and the formation of DNA-metabolite adducts. Moreover, the viability assays obtained for the L929 cell culture showed that both azathioprine and degraded azathioprine induced a decrease in cell proliferation.

Immune Profiling of Peripheral Blood Mononuclear Cells at Pancreas Acute Rejection Episodes in Kidney-Pancreas Transplant Recipients.

Profiling of circulating immune cells provides valuable insight to the pathophysiology of acute rejection in organ transplantation. Herein we characterized the peripheral blood mononuclear cells in simultaneous kidney-pancreas transplant recipients. We conducted a retrospective analysis in a biopsy-matched cohort (n = 67) and compared patients with biopsy proven acute rejection (BPAR; 41%) to those without rejection (No-AR). We observed that CD3+ T cells, both CD8+ and CD4+, as well as CD19+ B cells were increased in patients with BPAR, particularly in biopsies performed in the early post-transplant period (<3months). During this period immune subsets presented a good discriminative ability (CD4+ AUC 0.79; CD8+ AUC 0.80; B cells AUC 0.86; p < 0.05) and outperformed lipase (AUC 0.62; p = 0.12) for the diagnosis of acute rejection. We further evaluated whether this could be explained by differences in frequencies prior to transplantation. Patients presenting with early post-transplant rejection (<3months) had a significant increase in T-cell frequencies pre-transplant, both CD4+ T cells and CD8+ T cells (p < 0.01), which were associated with a significant inferior rejection-free graft survival. T cell frequencies in peripheral blood correlated with pancreas acute rejection episodes, and variations prior to transplantation were associated with pancreas early acute rejection.

Mycophenolate-Induced Hepatotoxicity Precipitates Tacrolimus Nephrotoxicity in a Kidney Transplant Recipient: A Case Report

Mycophenolate (mycophenolate mofetil [MMF]; mycophenolate sodium [MPS]) and tacrolimus (FK-506) are commonly and concomitantly used to prevent rejection in organ transplant. Mycophenolate-induced hepatotoxicity causing the reduced FK-506 metabolism with nephrotoxicity may be less appreciated, leading to inappropriate management. We describe a new living donor kidney recipient receiving pretransplant and post-transplant immunosuppressants including oral mycophenolate (MMF 1 g daily) and tacrolimus (FK-506 4-8 mg daily) who developed progressive liver dysfunction (up to 10-fold increase) despite the reduced FK-506 dosage (6 mg daily). A thorough investigation including infection, inflammation, and autoimmune hepatitis were unremarkable. With a withdrawal of MMF, his liver function improved, but persistently higher trough serum FK-506 level (12-15 ng/mL) and increased serum creatinine were notable. Moreover, the reintroduction of MPS with the reduced FK-506 dosage (4 mg daily) worsened liver function along with FK-506 nephrotoxicity (serum creatinine from 1.4-2.4 mg/dL). The replacement of MPS with mammalian target of rapamycin inhibitor not only resolved liver injury but also normalized serum FK-506 level and kidney function. Mycophenolate should be kept in mind as a cause of drug-induced hepatotoxicity that can reduce tacrolimus metabolism, leading to FK-506 nephrotoxicity and acute kidney injury in organ transplant.

Estimation of Antibody-Verified Eplet Mismatch Load, 2-Field HLA Resolution vs Imputation in a Large Cohort of European Donors

The assessment of class II eplet mismatch load is useful to determine the risk of chronic rejection in solid organ transplantation. However, high-resolution (2-field) HLA typing is mandatory to accurately define eplet mismatches. The imputation of the most frequent allele has been used in retrospective studies. Here, we sought to investigate the concordant of antibody-verified (AbV) eplet load in different class II alelles between real 2-field HLA typing and HLA imputed by most frequent allele in a large White cohort. The allelic frequency of the different HLA class II loci was calculated using a database of high-resolution typing of 23,628 voluntary Spanish bone marrow donors obtained from the Spanish Registry of Bone Marrow Donors, managed by the Josep Carreras Foundation. The AbV eplet count in the different class II alleles was performed using the HLA-Matchmaker v3.1 algorithm. The probability of imputing the correct allele compared to the most frequent for DRB1 and DQB1 loci was 69.3% and 53.0%, respectively. However, studying the less frequent alleles, the same AbV eplet load was observed in 82.22% and 76.15%, respectively. Our data show that despite the potential error in the imputation of class II HLA typing, the number of AbV eplets is not significantly over- or underestimated in our population. Until high-resolution typing is widely established for solid organ transplantation, retrospective studies of AbV eplet mismatch load with imputed high-resolution types provide an acceptable outcome in White people.

TNFRSF13B in B cell responses to organ transplantation

Antibodies directed against organ transplants are thought to pose the most vexing hurdle to enduring function and survival of the transplants, particularly organ xenotransplants, and accordingly basic and clinical investigation has focused on elucidating the specificity and pathogenicity of graft-specific antibodies. While much has been learned about these matters, far less is known about the B cells producing graft-specific antibodies and why these antibodies appear to injure some grafts but not others. With the goal of addressing those questions, we have investigated the properties of tumor necrosis factor receptor super family-13B (TNFRSF13B), which regulates various aspects of B cell responses. A full understanding of the functions of TNFRSF13B however is hindered by extreme polymorphism and by diversity of interactions of the protein. Nevertheless, TNFRSF13B variants have been found to exert distinct impact on natural and elicited antibody responses and host defense and mutations of TNFRSF13B have been found to influence the propensity for development of antibody-mediated rejection of organ transplants. Because B cell responses potentially limit application of xenotransplantation, understanding how TNFRSF13B diversity and TNFRSF13B variants govern immunity in xenotransplantation could inspire development of novel therapeutics that could in turn accelerate clinical implementation of xenotransplantation.

Liquid chromatographic methods in the determination of inosine monophosphate dehydrogenase enzyme activity: a review.

Inosine monophosphate dehydrogenase (IMPDH) is a crucial enzyme involved in the de novo synthesis of purine nucleotides. IMPDH activity is used to evaluate the pharmacodynamics/pharmacokinetics of immunosuppressant drugs such as mycophenolic acid and thiopurines. These drugs are often used to prevent organ transplant rejection and as steroid-sparing agents in autoinflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis. Numerous analytical techniques have been employed to evaluate IMPDH activity in biological matrices. However, hyphenated LC techniques were most widely used in the literature. This review focuses on hyphenated LC methods used to measure IMPDH activity and provides detailed insight into the sample preparation techniques, chromatographic conditions, enzymatic assay conditions, detectors and normalization factors employed in those methods.

Dysbiosis of the Female Murine Gut Microbiome Exacerbates Neutrophil-mediated Vascular Allograft Injury by Affecting Immunoregulation by Acetate.

The gut microbiota affects immune responses that cause organ transplant rejection, but the mechanisms by which this occurs remain poorly understood. We have examined, in a murine model, how disruption of the gut microbiota with antibiotics early in life alters this microbial community later in life to affect immune responses that injure vascular allografts. Analysis of 16S rRNA and whole genome sequencing of the gut microbiota demonstrated that early life disruption of this microbial community with antibiotics caused a reduction in taxa and enzymatic genes involved in the synthesis of acetate, an immunoregulatory metabolite in mice and humans. When allograft vascular injury was examined, early life disruption of the gut microbiota increased neutrophil accumulation and related medial injury of transplanted arteries. Normalizing the gut microbiota by co-housing and oral administration of acetate prevented neutrophil-mediated vascular allograft injury. Dysbiosis of the gut microbiome that reduces its production of the immunoregulatory metabolite acetate exacerbates neutrophil-mediated allograft vascular injury.

Preparation and evaluation of PLGA-PEG/Gusperimus nanoparticles as a controlled delivery anti-inflammatory drug

Gusperimus is an immunosuppressive drug used to control autoimmune diseases and prevent rejection in organ transplantation. It has a high-water solubility leading to poor intracellular permeability, rapid enzymatic degradation, and clearance. To achieve controlled delivery of Gusperimus and protect its stability and bioactivity, encapsulation in PLGA-PEG nanoparticles was studied. The effect on nanoparticles properties of the surfactant type (Pluronic® F127, P84, and F108) and polymer concentration (0.2% and 1.7% w/v) used for their preparation was evaluated. The system prepared with 1.7% w/v PLGA-PEG and 1% w/v Pluronic® F127 was selected to encapsulate Gusperimus since it provides the smallest particle size and higher colloidal stability. The nanoparticles showed an encapsulation efficiency and a load capacity of 82.8% and 1.48%, respectively. In vitro release showed a total release of 19% after 36 h. PLGA-PEG/Gusperimus nanoparticles were evaluated in vitro to determine their cytotoxicity, cellular uptake, and anti-inflammatory activity in mouse macrophages. They showed no-cytotoxicity for J774A.1 macrophages with 100% viability, for concentrations up to 50 μg/mL and higher than 75% for 400.0 μg/mL. PLGA-PEG/Gusperimus nanoparticles were taken up by macrophages and exerted anti-inflammatory effects as it is indicated by nitric oxide reduction and cytokine suppression in LPS-induced inflammatory macrophages model.