Small Molecule/HLA Complexes Alter the Cellular Proteomic Content

A medical product usually undergoes several clinical trials, including the testing of volunteers. Nevertheless, genomic variances in the patients cannot be considered comprehensively and adverse drug reactions (ADRs) are missed or misinterpreted during trials. Despite the relation between ADRs and human leukocyte antigen (HLA) molecules being known for several years, the fundamental molecular mechanisms leading to the development of such an ADR often remains only vaguely solved. The analysis of the peptidome can reveal changes in peptide presentation post-drug treatment and explain, for example, the severe cutaneous ADR in HLA-B*57:01-positive patients treated with the antiretroviral drug abacavir in anti-HIV therapy. However, as seen in the biophysical features of HLA-A*31:01-presented peptides, treatment with the anticonvulsant carbamazepine only induces minor changes. Since the binding of a drug to a certain HLA allelic variant is extremely distinct, the influence of the small molecule/protein complex on the proteomic content of a cell becomes clear. A sophisticated methodology elucidating the impact of drug treatment on cells is a full proteome analysis. The principal component analysis of abacavir, carbamazepine or carbamazepine-10,11-epoxid treated cells reveals clear clustering of the drug-treated and the untreated samples that express the respective HLA molecule. Following drug treatment, several proteins were shown to be significantly up- or downregulated. Proteomics and peptidomics are valuable tools to differential clinical outcomes of patients with the same HLA phenotype.

DE NOVO AUTOIMMUNE HEPATITIS AFTER LIVER TRANSPLANTATION IN CHILDREN. REVIEW

De novo autoimmune hepatitis (AIH) is a clinical disease similar to AIH that develops in liver transplant recipients with diseases other than AIH. Timely recognition of this disease makes it possible to avoid graft rejection and liver re-transplantation (LT), liver fibrosis, and can ensure a long life expectancy, given the effectiveness of more active immunosuppression with the use of corticosteroids and azathioprine, as in the treatment of idiopathic AIH. The de novo prefix was added to distinguish this condition from primary autoimmune hepatitis prior to transplant, but the diagnostic algorithm adopted generally accepted diagnostic criteria for autoimmune hepatitis. In fact, de novo autoimmune hepatitis is characterized by typical necroinflammation of the liver, rich in plasma cells, increased serum gammaglobulin levels, and the appearance of inorganic specific autoantibodies. However, the general signs of autoimmune hepatitis de novo, apparently, cannot be associated with an unambiguous pathophysiological pathway, since they can develop in patients undergoing liver transplantation due to different etiologies. The literature review presents such aspects as the prevalence of this case, the influence of the HLA phenotype on the manifestation and outcome of the disease, diagnosis and treatment. Objective. To conduct a literary meta-analysis of scientific publications on the development of De novo Autoimmune hepatitis after liver transplantation in children. Materials and methods. The authors selected scientific bases for the search such as: Web of science, Cyberleninka, UpToDate, Pubmed and Cochrane, Google Scholar. Results. A meta-analysis of scientific articles in English and Russian was carried out for the selected keywords. The causes of development were not infectious or surgical complications. Liver biopsy revealed histological changes typical of acute or chronic ovulation. High levels of transaminases, hypergammaglobulinemia, positivity to autoantibodies – ANA, AMA, SMA, anti-LKM-1. De novo AIH patients did not respond to conventional anti-rejection therapy, but responded only to classical AIH therapy.

Highly Sensitized Patients Are Well Served by Receiving a Compatible Organ Offer Based on Acceptable Mismatches

Highly sensitized kidney patients accrue on the transplant waiting list due to their broad immunization against non-self Human Leucocyte Antigens (HLA). Although challenging, the best option for highly sensitized patients is transplantation with a crossmatch negative donor without any additional therapeutic intervention. The Eurotransplant Acceptable Mismatch (AM) program was initiated more than 30 years ago with the intention to increase the chance for highly sensitized patients to be transplanted with such a compatible donor. The AM program allows for enhanced transplantation to this difficult to transplant patient group by allocating deceased donor kidneys on the basis of a match with the recipient’s own HLA antigens in combination with predefined acceptable antigens. Acceptable antigens are those HLA antigens towards which the patients has never formed antibodies, as determined by extensive laboratory testing. By using this extended HLA phenotype for allocation and giving priority whenever a compatible donor organ becomes available, organ offers are made for roughly 80% of patients in this program. Up till now, more than 1700 highly sensitized patients have been transplanted through the AM program. Recent studies have shown that the concept of acceptable mismatches being truly immunologically acceptable holds true for both rejection rates and long-term graft survival. Patients that were transplanted through the AM program had a similar rejection incidence and long-term graft survival rates identical to non-sensitized patients transplanted through regular allocation. However, a subset of patients included in the AM program does not receive an organ offer within a reasonable time frame. As these are often patients with a rare HLA phenotype in comparison to the Eurotransplant donor population, extension of the donor pool for these specific patients through further European collaboration would significantly increase their chances of being transplanted. For those patients that will not benefit from such strategy, desensitization is the ultimate solution.

Tackling HLA Deficiencies Head on with Oncolytic Viruses

Dysregulation of HLA (human leukocyte antigen) function is increasingly recognized as a common escape mechanism for cancers subject to the pressures exerted by immunosurveillance or immunotherapeutic interventions. Oncolytic viruses have the potential to counter this resistance by upregulating HLA expression or encouraging an HLA-independent immunological responses. However, to achieve the best therapeutic outcomes, a prospective understanding of the HLA phenotype of cancer patients is required to match them to the characteristics of different oncolytic strategies. Here, we consider the spectrum of immune competence observed in clinical disease and discuss how it can be best addressed using this novel and powerful treatment approach.

Association of human leukocyte antigen groups with oral mucositis in patients undergoing bone marrow transplantation

Background: Oral mucositis (OM) after hematopoetic stem cell transplantation (HSCT) may lead to toxicity that impair quality of life. Associations between some diseases and human leukocyte antigen (HLA) groups have been long recognized. A genetic contribution as the association of HLA groups with OM after HSCT, has not been reported to date. We aimed to assess whether an association of HLA phenotype and OM after allogeneic HSCT exists.Methods: This was a prospective observational study in which OM was assessed with clinical questioning and examination. Association of OM with gender, age, HLA phenotypes, diagnosis, conditioning regimen, stem cell source, engraftment times, and complications was investigated.Results: 45 patients were enrolled. All the patients with HLA-B44 phenotype developed mild OM, while all patients with HLA-DR15 phenotype developed severe OM. HLA-A23, HLA-B21, HLA-B44, HLA-DR15, and HLA-DR11 were associated with shorter OM duration. HLA-A26 and HLA-B52 were associated with longer OM duration. Myeloablative conditioning regimen and longer duration of neutropenia were associated with longer OM duration. Regression analysis revealed HLA-B44 and HLA-DR11 as independent factors associated with milder OM.Conclusion: We identified that some HLA alleles correlated with OM severity and duration. These findings may facilitate predicting risk of morbidity and may provide incorporation of individualized preventive and treatment approaches.

Association Of Multispecific Red Blood Cell Alloimmunization With HLA-Class II Variants is Related to Mjor RhD Phenotypes

Background It remains unclear why only some patients form alloantibodies against foreign RBC antigens. Transfusion of red blood cell (RBC) products and pregnancy are the most relevant causes of immunization against RBC alloantigens. Here we investigated the relationship between RBC alloantibodies, Rh phenotype, and HLA phenotype among patients with multiple RBC alloantibodies Methods In a group of 124 multi-responders—including both pregnant women and transplant recipients—we analyzed the distribution of HLA-Class II variants in subgroups of multi-responders to RBC alloantigens according to their Rh status. Results As expected, the RhD-negative phenotype was overrepresented in our alloimmunized group (49.2%) compared to in the general population. Importantly, HLA-DRB1*15 carriers were significantly overrepresented among D-negative multi-responders compared to D-positive multi-responders (Pc = 0.045). Furthermore, the linked HLA-DRB1*13, HLA-DQB1*06, and HLA-DQA1*01 variants were more frequent in individuals with the DCCee phenotype than in other RhD-positive phenotypes. Conclusion Our present findings showed that RBC multispecific alloimmunization was associated with particular HLA-Class II variants based on Rh status.

Peculiarities of phenotypes of patients with pyelo- and glomerulonephritis by HLA distribution analysis

Studies devoted to the role of human leucocyte antigens (HLA) in pathogenesis of chronic kidney disease (CKD) have demonstrated the associative links of the HLA antigens, which stipulate the relative and attributive risks of some autoimmune diseases, with immune disorder and a high production of pro-inflammatory cytokines. The aim of our study was to determine the peculiarities of phenotypes of CKD patients according to the distribution of HLA-A, B and DR antigens and to conduct their comparative analysis in patients with pyelonephritis (PN) and glomerulonephritis (GN). Methods: The distribution of HLA-A, B, DR antigens in 384 CKD patients (120 with PN and 264 with GN) was analyzed. HLA antigens were defined using a standard microlymphocytotoxic test on the Terasakiґs planchette with special panels of anti-HLA serums (20 antigens of locus A, 31 – B and 9 – DR). The control group consisted of 350 healthy donors. The HLA antigen frequencies in normal and diseased subjects were compared taking each antigen separately, using χ2 test. The etiologic fraction (attributive risk s > 0,1) was counted using the formula: s = x - y/I- y, where x is frequency of antigen in patients and y is frequency in healthy. The s reading was considered reliable when it exceeded 0.1. Results. The causal role (σ > 0,1) was determined for А10, А11; В14, В16 for PN; antigens-protectors - А2, В21, В35, В40. For CGN, NS the relative risk is high (RR > 2) at the presence of HLA-A23, А24, А28; B8, В38, В41, В44; DR1, DR4, DRw52 in phenotype, the causal role in etiopathology (σ>0.1) is indicated for A24,А28; B8; DR1, DR4, DRw52; the disease protectors are B12 and B16. Conclusion. Conclusion. The features of the HLA-phenotype of patients with pyelo- and glomerulonephritis were shown. It allowed to establish the interconnectedness of the antigens of the histocompatibility complex with the risk of kidney diseases developing, which could help to personificate of the treatment and predicte of the course of the disease.

ASSOTIATIONS OF PECULIARITIES OF HLA-PHENOTYPE AND THE SENSIBILITY TO THE CORTICOSTEROID TREATMENT IN PATIENTS WITH CHRONIC GLOMERULONEPHRITIS WITH NEPHROTIC SYNDROME

The purpose of study was determination of HLA -antigens I and II classes as predictors of ineffectiveness of initial steroid therapy, and according prognozonegative markers of chronic glomerulonephritis with nephrotic syndrome. Methods. In 59 chronic glomerulonephritis with nephrotic syndrome patients (steroid sensitive n=33 (1 gr.) and steroid resistant’s n= 26 (2 gr.)) and 350 healthy donors( control group) studied HLA antigens I and II classes of the special anti- HLA-antigens panel (20 antigens of locus A, 31 – of locus B and 9- of locus DR). Result. In patients with chronic glomerulonephritis, nephrotic syndrome with hormone sensitivity relative risk is high at the presents of A28 (RR=8,5, r р <0,001), it made attributive risk (=0,37). In comparison with a control group, RR>2 for antigens A11 (RR=2,23), A23 (RR=4,28), A24 (RR=3,3), A29 (RR=10,78) that A30 (RR=11,23); attributive risk more than 0,1 for the antigen A11 (=0,16) ; A24 (=0,13), other did not differ from control. Subzero connection is exposed for the antigens of A2 (р<0,001), А9 (р=0,007). In locus antigen B14 (RR=5,65, р =0,001) are exposed, B44 (RR=48,25, р =0,004), B51(RR=12,32, р =0,006) and attributive risk of development of disease (according =0,24, 0,12 ; 0,14); and antigens B38 and B41 (RR=11,57, р=0,05). The steroid sensitivity was associated with the antigens B5 (p=0,033), B12 (p=0,005) and B35 (p=0,021). In locus DR made etiologic faction antigens DR4 (RR=7,0 and =0,24) DRw52 (RR=7,0 and =0,25). Conclusions. For patients with chronic glomerulonephritis with a nephrotic syndrome antigens of HLA-B14,B38, B51, DRw52 are associated with steroid sensitivity. The attributive risk of steroid resistance is high for split A19+31+32, antigens B8, B55.