HLA-B Alleles Research Articles

Distinct Plasma Concentrations of Acyl-CoA-Binding Protein (ACBP) in HIV Progressors and Elite Controllers.

HIV elite controllers (ECs) are characterized by the spontaneous control of viral replication, and by metabolic and autophagic profiles which favor anti-HIV CD4 and CD8 T-cell responses. Extracellular acyl coenzyme A binding protein (ACBP) acts as a feedback inhibitor of autophagy. Herein, we assessed the circulating ACBP levels in ECs, compared to people living with HIV (PLWH) receiving antiretroviral therapy (ART) or not. We found lower ACBP levels in ECs compared to ART-naïve or ART-treated PLWH (p < 0.01 for both comparisons), independently of age and sex. ACBP levels were similar in ECs and HIV-uninfected controls. The expression of the protective HLA alleles HLA-B*27, *57, or *58 did not influence ACBP levels in ECs. ACBP levels were not associated with CD4 or CD8 T-cell counts, CD4 loss over time, inflammatory cytokines, or anti-CMV IgG titers in ECs. In ART-treated PLWH, ACBP levels were correlated with interleukin (IL)-1β levels, but not with other inflammatory cytokines such as IL-6, IL-8, IL-32, or TNF-α. In conclusion, ECs are characterized by low ACBP plasma levels compared to ART-naïve or ART-treated PLWH. As autophagy is key to anti-HIV CD4 and CD8 T-cell responses, the ACBP pathway constitutes an interesting target in HIV cure strategies.

Seroprevalence of diphtheria and measles antibodies and their association with demographics, self-reported immunity, and immunogenetic factors in healthcare workers in Latvia

Latvia is among European countries with outbreaks of diphtheria and measles. Healthcare workers (HCW) are exposed to infections and can transmit them to unvaccinated patients. We assessed the seroprevalence of antibodies against diphtheria and measles and their association with demographics, self-reported immunity, the presence of the HLA-B27 allele, and level of interferon regulatory factor 5 (IRF5) in Latvian HCW. Anti-diphtheria and anti-measles IgG antibodies and the level of IRF5 in serum were tested by enzyme immunoassay. The presence of the HLA-B27 allele was detected by a real-time polymerase chain reaction. The study involved 176 HCW, including 29% doctors and 44% nurses. Among HCW, 95.5% were seropositive for diphtheria. However, only 65.9% had full seroprotection against it. The seronegativity for measles (21.6%) was higher than for diphtheria (4.5%) without differences in gender and medical staff groups. Older age was associated with waning immunity against diphtheria and a higher rate of seropositivity for measles. Considered immunogenetic factors did not affect the level of antibodies, and variability of the level of IRF5 in serum can reflect ageing processes. Self-reported vaccination status had a low informative value regarding full seroprotection against diphtheria and seropositivity for measles indicating the need for pre-vaccination IgG screening in planning the booster vaccination.

Potential role of regulatory DNA variants in modifying the risk of severe cutaneous reactions induced by aromatic anti-seizure medications.

ObjectiveStevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions. Antiseizure medications (ASMs) with aromatic ring structure, including carbamazepine, are among the most common culprits. Screening for human leukocyte antigen (HLA) allele HLA‐B*15:02 is recommended prior to initiating treatment with carbamazepine in Asians, but this allele has low positive predictive value.MethodsWe performed whole genome sequencing and analyzed 6 199 696 common variants among 113 aromatic ASM‐induced SJS/TEN cases and 84 tolerant controls of Han Chinese ethnicity.ResultsIn the primary analysis, nine variants reached genome‐wide significance (p < 5e‐08), one in the carbamazepine subanalysis (85 cases vs. 77 controls) and a further eight identified in HLA‐B*15:02‐negative subanalysis (35 cases and 53 controls). Interaction analysis between each novel variant from the primary analysis found that five increased risk irrespective of HLA‐B*15:02 status or zygosity. HLA‐B*15:02‐positive individuals were found to have reduced risk if they also carried a chromosome 12 variant, chr12.9426934 (heterozygotes: relative risk = .71, p = .001; homozygotes: relative risk = .23, p < .001). All significant variants lie within intronic or intergenic regions with poorly understood functional consequence. In silico functional analysis of suggestive variants (p < 5e‐6) identified through the primary and subanalyses (stratified by HLA‐B*15:02 status and drug exposure) suggests that genetic variation within regulatory DNA may contribute to risk indirectly by disrupting the regulation of pathology‐related genes. The genes implicated were specific either to the primary analysis (CD9), HLA‐B*15:02 carriers (DOCK10), noncarriers (ABCA1), carbamazepine exposure (HLA‐E), or phenytoin exposure (CD24).SignificanceWe identified variants that could explain why some carriers of HLA‐B*15:02 tolerate treatment, and why some noncarriers develop ASM‐induced SJS/TEN. Additionally, this analysis suggests that the mixing of HLA‐B*15:02 carrier status in previous studies might have masked variants contributing to susceptibility, and that inheritance of risk for ASM‐induced SJS/TEN is complex, likely involving multiple risk variants.

Human leucocyte antigens profiling in Malay female patients with systemic lupus erythematosus: are we the same or different?

ObjectiveSLE is a heterogeneous autoimmune disease, in terms of clinical presentation, incidence and severity across diverse ethnic populations. We investigated the human leucocyte antigens (HLA) profile (ie, HLA-A, HLA-B and...

Description of two new alleles: HLA-B*50:79 and HLA-DRB1*04:332.

Two novel HLA alleles HLA-B*50:79 and -DRB1*04:332 have non-synonymous mutations in exon 4 and exon 3, respectively.

Clinical significance of detecting human leukocyte antigen class I allele-lacking leukocytes in aplastic anemia

Human leukocyte antigen (HLA) class I allele-lacking [HLA (-)] leukocytes provide compelling evidence that cytotoxic T-lymphocytes are involved in the development of aplastic anemia (AA). However, the clinical significance and precise mechanisms underlying clonal hematopoiesis by HLA (-) hematopoietic stem progenitor cells remain unknown. In HLA (-) cells from patients with AA, we discovered a common nonsense mutation at codon19 (c.19C>T, p.R7X) in exon1 (Exon1mut) of different HLA-A and HLA-B alleles. Exon1 mutation detection using droplet digital polymerase chain reaction (ddPCR) is a powerful tool for diagnosing immune pathophysiology in patients with bone marrow failure. We also looked at the prognosis of 633 patients with AA, including 127 with HLA (-) leukocytes who had been followed up for a long time. In Japanese patients with AA, HLA (-) leukocytes and concomitant aberrant clones were not associated with clonal evolution to MDS/AML. In patients with AA and both marker (-) leukocytes, HLA (-) leukocytes may indicate a lower risk of developing secondary paroxysmal nocturnal hemoglobinuria (PNH). Detecting HLA (-) leukocytes is critical for managing patients with AA and assisting physicians in selecting appropriate therapy.

Human leukocyte antigen-B alleles in spondyloarthritides: A single-center, prospective, cross-sectional study

Objective: The objective of this study is to study distribution of human leukocyte antigen (HLA)-B alleles in Spondyloarthritis (SpA) and to find its clinical relevance in the patient management.Materials and Methods: A prospective, cross-sectional, pilot study was carried out on 100 participants at the single center of Northern India (Sir Ganga Ram Hospital, New Delhi). Assessment in ankylosing spondylitis (ASAS) classification criteria for axial/peripheral spondyloarthritis (SPA) (conventionally AS-ankylosing spondylitis), classification criteria for reactive arthritis (ReA), and CASPAR (classification criteria for psoriatic arthritis) criteria for psoriatic arthritis were used to sub-classify patients. Inflammatory bowel disease (IBD) patients who classified for ASAS criteria for SPA were classified as IBD-related SPA. Demographic data, disease characteristics, and relevant investigations were noted. HLA-B genotyping was carried out by the polymerase chain reaction method. HLA-B genotyping of 100 healthy kidney transplant donors were taken as controls. Fisher's exact test was used. P < 0.05 was considered as statistically significant.Results: Out of 100 patients, 58 were male and 42 were female. SPA (AS), ReA, PSA, and IBD-related SPA were 65, 12, 16, and 07, respectively. HLA-B 27+ve participants were 57. HLA-B40 and HLA-B52 were present in 25 and 19 participants, respectively. HLA-B27 allele was associated with SPA, PSA, and IBD-related SPA (P < 0.01, 0.034, and 0.037, respectively). In HLA-B27-ve cases, the frequency of HLA-B40 was increased (P value – 0.033, odds ratio [OR] with 95% confidence interval-2.44, [1.09, 5.48]). Similarly, the frequency of HLA-B15 and HLA-B13 were increased in PSA (P value – 0.034, 0.020 with OR – 4.09, 6.33, respectively). The presence of HLA-B27 allele favored axial ± peripheral disease while its absence favored peripheral disease (P value– 0.019). HLA-B27+ve participants had more active disease compared to HLA-B27-ve and HLA-B40+ve cases (P < 0.01 and 0.013, respectively).Conclusion: The utility of HLA-B alleles other than HLA-B27 is limited in SpA patients' management. To find their use in diagnosis, prognosis and treatment need further studies.xs

Identification of five novel HLA‐B alleles in donors from the Colombian Bone Marrow Donor Registry

Identification of five novel HLA-B alleles in five samples from Colombian bone marrow donors.

Global Meta-Analysis on the Association between Behcet Syndrome and Polymorphisms from the HLA Class I (A, B, and C) and Class II (DRB1, DQB1, and DPB1) Genes.

Behcet syndrome (BS) is a multisystemic perivasculitis whose genetic susceptibility is linked to HLA region. We first meta-analysed all HLA class I and II genes involved in BS susceptibility in all ethnic groups worldwide. We identified 1141 articles and finally included 31 case-control studies after multiple rounds of selection. We analysed frequencies for 24 HLA-A alleles (3 alleles for HLA-A∗26 at four digits), 50 HLA-B alleles (11 alleles for HLA-B∗51 at four digits), 15 HLA-C alleles, 16 HLA-DRB1 alleles, 6 HLA-DQB1 alleles, and 15 HLA-DPB1 alleles. We meta-analysed only HLA allelic frequencies from at least three studies; therefore, we investigated 21 alleles out of 140. Going from 7.00 to 1.6 OR, we found 11 class I alleles conferring risk for BS: B∗51 : 08, B∗51, B∗51 : 01, B∗51 : 02, DQB1∗03, A∗26 : 01, Cw∗14, Cw∗15, Cw∗16, B∗15, and A∗26. Overall, the studies included populations from Europe (Greece, Spain, Italy, Germany, and Ireland), Asia (Korea, China, China Han, and Thailand), Middle East (Israel, Saudi Arabia, and Iran), and Morocco (as no other North-African population was included). We collected a number of ethnical groups sufficient to conduct an ethnic-specific meta-analysis where Europeans showed 11.25 OR for B∗51:08 and Japan 3.50 OR for A∗26 : 01. A remarkable result was that the most frequent HLA − B∗51 two-digit alleles associated with BS were different among populations: HLA − B∗51 : 08 in Europe, HLA − B∗51 : 01 in Turkey, and HLA − B∗51 : 02 in Japan. Overall, we discussed our real-world results with other imputation studies.

Association of HLA-B∗35 and moderate or severe cutaneous reactions secondary to benznidazole treatment in chronic chagas disease

ObjectivesBenznidazole is the first-line treatment for Chagas disease. Adverse events appear in more than 50% of patients, leading to discontinuation in approximately 15%. Cutaneous reactions are one of the most frequent adverse events. Human leucocyte antigen (HLA) genotyping studies identified an association between cutaneous reactions to benznidazole and carrying the specific allele HLA-B∗35:05. We designed the present study to prospectively confirm this association. MethodsThis is a prospective observational study including Chagas disease patients aged 18 years or more who accepted to receive benznidazole treatment following current guidelines. Allele genotyping of HLA-B was determined in all patients. Clinical and analytical follow up was performed at days 0, 7, 14, 30 and 60 of treatment. ResultsTwo-hundred and seven individuals were included. Seventy per cent were female with a mean age of 45.1 (SD ± 9.86) years mainly from Bolivia (92.8%). In 102 (49.3%) cases a cutaneous reaction was diagnosed. Forty-eight (46.6%) were classified as mild, 37 (35.9%) as moderate and 18 (17.5%) as severe. Thirty-two (15.4%) patients had to definitively interrupt the treatment because of a cutaneous reaction. Female sex (OR 4.49; 95% CI 1.62–12.47), new-onset eosinophilia before cutaneous symptoms (OR 2.55; 95% CI 1.2–5.43) and carrying the HLA-B∗35 allelic group (OR 2.58; 95% CI 1.2–5.51) were all predictors of moderate to severe cutaneous reactions. No statistical significance was found when the specific allele HLA-B∗35:05 was analysed. ConclusionsPatients carrying the HLA-B∗35 allelic group are at higher risk of moderate to severe reactions when taking benznidazole treatment.

Computational antigenic epitope prediction of clinical Indonesian Dengue virus NS1 protein

The identification of human Non-Structural-1 (NS1) protein epitopes will help us better understand Dengue virus (DENV) immunopathogenesis. In this study, several online and offline bioinformatic prediction tools were exploited to predict and analyze T-cell and B-cell epitopes of DENV NS1 consensus sequences originated from Indonesian clinical isolates. We identified a potential peptide at NS1155--163 (VEDYGFGIF) which interact with MHC-I allele HLA-B*40:01 and showed high binding affinity (IC50) scores ranging between 63.8 nM to 183.9 nM for all Indonesian DENV serotypes. Furthermore, we have succeeded identified a region at the C-terminal of Indonesian DENV NS1 protein between 325--344 as part of discontinuous antigenic epitope which conserved for all serotypes. Our analyses showed this region could induce strong and persistent antibody against all DENV serotypes by interacting with MHC-I molecule and also recognized by B-cell receptor. The identification of DENV NS1 T-cell and B-cell epitopes may help in the development of a new vaccine, drug discovery, and diagnostic system to help eradicate dengue infection.

Can presence of HLA type I and II alleles be associated with clinical spectrum of CHIKV infection?

Host immune response and virulence factors are key to disease susceptibility. However, there are no known association studies of human leukocyte antigen (HLA) class I and II alleles with chikungunya virus (CHIKV) infection in the Latin American population. Here, we aimed to identify HLA alleles present in patients with CHIKV infection versus healthy controls as well as the allelic association with the clinical spectrum of the disease. We conducted a cross-sectional analysis of a community cohort and included patients aged 18 years and older with serologically confirmed CHIKV infection. HLA typing of HLA-A, HLA-B, and HLA-DRB1 alleles was performed. Two-by-two tables were used to establish associations between allele presence and clinical characteristics. Data from 65 patients with confirmed CHIKV infection were analyzed for HLA typing. CHIKV infection was significantly associated with the presence of HLA-A*68 [p=.005; odds ratio (OR): 8.90; 95% confidence interval (CI): 1.88-42.13], HLA-B*35 (p=.03; OR: 2.01; 95% CI: 1.06-3.86), HLA-DRB*01 (p<.001; OR: 5.70; 95% CI: 1.95-16.59), HLA-DRB1*04 (p<.001; OR: 7.37; 95% CI: 3.33-16.30), and HLA-DRB1*13 (p=.004; OR: 3.75; 95% CI: 1.50-9.39) alleles in patients versus healthy subjects. A statistically significant relationship was found between the presence of a rash on the face or abdomen and the presence of HLA-DRB1*04 (p=.028; OR: 3.2; 95% CI: 1.11-9.15 and p=.007; OR: 4.33; 95% CI: 1.45-12.88, respectively). Our study demonstrated that, in our cohort, HLA type I and type II alleles are associated with CHIKV infection, and an HLA type II allele is associated with dermatological symptoms. Further research is needed to establish a path for future investigation of genes outside the HLA system to improve knowledge of the pathophysiology of CHIKV infection and its host-pathogen interaction.

An HLA-I signature favouring KIR-educated Natural Killer cells mediates immune control of HIV in children and contrasts with the HLA-B-restricted CD8+ T-cell-mediated immune control in adults.

Natural Killer (NK) cells contribute to HIV control in adults, but HLA-B-mediated T-cell activity has a more substantial impact on disease outcome. However, the HLA-B molecules influencing immune control in adults have less impact on paediatric infection. To investigate the contribution NK cells make to immune control, we studied >300 children living with HIV followed over two decades in South Africa. In children, HLA-B alleles associated with adult protection or disease-susceptibility did not have significant effects, whereas Bw4 (p = 0.003) and low HLA-A expression (p = 0.002) alleles were strongly associated with immunological and viral control. In a comparator adult cohort, Bw4 and HLA-A expression contributions to HIV disease outcome were dwarfed by those of protective and disease-susceptible HLA-B molecules. We next investigated the immunophenotype and effector functions of NK cells in a subset of these children using flow cytometry. Slow progression and better plasma viraemic control were also associated with high frequencies of less terminally differentiated NKG2A+NKp46+CD56dim NK cells strongly responsive to cytokine stimulation and linked with the immunogenetic signature identified. Future studies are indicated to determine whether this signature associated with immune control in early life directly facilitates functional cure in children.

Critical Review of Gaps in the Diagnosis and Management of Drug-Induced Liver Injury Associated with Severe Cutaneous Adverse Reactions.

Drug-induced liver injury (DILI) encompasses the unexpected damage that drugs can cause to the liver. DILI may develop in the context of an immunoallergic syndrome with cutaneous manifestations, which are sometimes severe (SCARs). Nevirapine, allopurinol, anti-epileptics, sulfonamides, and antibiotics are the most frequent culprit drugs for DILI associated with SCARs. Interestingly, alleles HLA-B*58:01 and HLA-A*31:01 are associated with both adverse reactions. However, there is no consensus about the criteria used for the characterization of liver injury in this context, and the different thresholds for DILI definition make it difficult to gain insight into this complex disorder. Moreover, current limitations when evaluating causality in patients with DILI associated with SCARs are related to the plethora of causality assessment methods and the lack of consensual complementary tools. Finally, the management of this condition encompasses the treatment of liver and skin injury. Although the use of immunomodulant agents is accepted for SCARs, their role in treating liver injury remains controversial. Further randomized clinical trials are needed to test their efficacy and safety to address this complex entity. Therefore, this review aims to identify the current gaps in the definition, diagnosis, prognosis, and management of DILI associated with SCARs, proposing different strategies to fill in these gaps.

A new HLA-B allele, HLA-B*07:422.

The novel allele HLA-B*07:422 differs from HLA-B*07:02:01:01 by one nucleotide substitution in exon 4.

HLA-B*48:53, a novel HLA-B allele with two exonic mutations.

The novel HLA-B*48:53 allele was characterized using two next generation sequencing technologies.

The Copy Number of Disease-Associated HLA Alleles Predicts the Response to Immunosuppressive Therapy in Acquired Aplastic Anemia

In immune-mediated acquired aplastic anemia (AA), the presence of an HLA allele, which is highly overrepresented or lost due to somatic mutations, may represent a specific immune pathophysiology and a clinical manifestation. HLA-B*14:02 is one of the most overrepresented class I alleles in AA and is also frequently affected by a somatic loss of expression; the inherited B*14:02 genotype was correlated with high-risk clonal evolution in two independent cohorts in the U.S. (Babushok DV et al. Blood Adv 2017; Zaimoku Y et al. manuscript in preparation). In contrast, HLA-B*14:02 is virtually absent in Japanese, in whom somatic mutations of AA have frequently been detected in HLA-B*40:02, B*54:01, and A*02:06, and occasionally in A*02:01, A*02:07, A*31:01, B*13:01, B*40:01, B*40:03, B*44:03, B*55:02, and B*56:01 (Mizumaki H et al. Haematologica 2021). A class II allele HLA-DRB1*15 is highly overrepresented in AA across various ethnic groups, including those in the U.S. and Japanese. This retrospective study in the Japanese population aimed to explore the clinical significance of disease-associated non-B*14:02 HLA class I and II alleles in AA.A total of 423 enrolled patients with AA (very severe [n = 81], severe [n = 266], transfusion dependent non-severe [n = 76]; median age 60 [range, 1-86] years) had undergone genotyping for HLA-A, HLA-B, HLA-C, and HLA-DRB1 at 2-field resolution. The HLA allele frequencies in these patients were compared to those in a Japanese HLA haplotype dataset (n = 19183; Ikeda N et al. Tissue Antigens 2016).The most overrepresented allele in AA was HLA-DRB1*15:02, followed by DRB1*15:01, B*40:02, and A*02:06 (Table); DRB1*13:02 and B*44:03, which are in linkage disequilibrium, were markedly underrepresented, consistent with a well-known protective role of DRB1*13 against autoimmune diseases. HLA-DRB1*15:02 was also significantly correlated with age and its frequency among patients aged <50 years was below the level of the control group (Figure A). Frequencies of HLA-DRB1*15:01, B*40:02, and A*02:06 were increased in both older and younger groups. HLA-A*31:01 and A*02:01 found to be enriched in young patients instead of DRB1*15:02 (Figure B); B*13:01, B*55:02, and B*56:01 showed a similar tendency for an early onset. HLA-B*40:02 was correlated with disease severity and was especially overrepresented in very severe AA (Figure C).The overall response rate to anti-thymocyte globulin-based immunosuppressive therapy at 6 months was 63% (139 of 220 treated and evaluable patients). A trend for a higher response was observed in patients harboring mutation-related HLA-B alleles (except for minor alleles B*13:01, B*40:03, and B*55:02) and the highly overrepresented or protective HLA-DRB1 alleles, but not in the HLA-A alleles (Figure D). A multivariate logistic regression revealed that the combination of the presence of any favorable alleles in HLA-B (odds ratio 3.6, P < 0.0001) or in HLA-DRB1 (odds ratio 2.3, P = 0.00085) was significantly and independently associated with a hematologic response; the tendencies for a lower or higher response in very severe disease and the presence of paroxysmal nocturnal hemoglobinuria clone did not reach statistical significance. Further, there was likely an additive effect when two favorable alleles coexisted in HLA-B or HLA-DRB1 (Figure E); the copy number of the favorable HLA-B and HLA-DRB1 alleles stratified the response rate to four groups: three or four copies, 95% (19 of 20); two copies, 72% (61 of 85); one copy, 59% (50 of 85); and zero copy, 30% (9 of 30). Only eight patients displayed clonal evolution to monosomy 7, myelodysplastic syndrome, or acute myeloid leukemia after immunosuppression without significant overrepresentation or underrepresentation of the pathogenic HLA alleles.Using a large dataset of homogeneous Japanese population with high-resolution HLA typing, we revealed, for the first time, a strong relationship between disease-associated (overrepresented, inactivated, or protecting) HLA alleles and the responsiveness to immunosuppressive therapy. [Display omitted] DisclosuresTakamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; SRL: Consultancy; Adaptive Biotechnologies, Eisai: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Yamazaki: Novartis Pharma: Honoraria; Kyowa Kirin: Honoraria; Kyowa Kirin: Research Funding. Nakao: Symbio: Consultancy; Kyowa Kirin: Honoraria; Novartis Pharma: Honoraria; Alexion Pharma: Research Funding.

Successful Treatment with ALVR105 for Disseminated Adenovirus Infection in an Infant after Allogeneic Hematopoietic Cell Transplantation: A Case Report

Background: Adenovirus (AdV) disease is one of the most difficult-to-manage complications in infants and children who have received allogeneic hematopoietic cell transplantation (HCT). Cidofovir has been used off-label as preemptive anti-adenoviral therapy. It is the current standard of care treatment, but data supporting its therapeutic value are lacking, and its use is limited by severe renal toxicity.Case: A 10-month-old male with infantile osteopetrosis underwent a single-unit umbilical cord blood transplant (TNC = 21.78 × 10 7/kg, CD34 = 10.5 × 10 5/kg) after myeloablative conditioning (busulfan, cyclophosphamide, and anti-thymocyte globulin). Cyclosporine and mycophenolate mofetil (MMF) were used for graft versus host disease (GVHD) prophylaxis. A positive test for adenovirus from a respiratory viral panel pre-transplant delayed conditioning for six weeks until the patient had two negative tests, one week apart. His post-transplant course was complicated by severe veno-occlusive disease starting on day +3, with secondary respiratory and renal failure. The patient was started on continuous renal replacement therapy along with intravenous defibrotide and high-dose steroids. Neutrophil engraftment did not occur until day +38. Post-engraftment, the patient developed a skin rash diagnosed as GVHD by biopsy, which was treated with corticosteroids at 2 mg/kg/day. As part of viral infection surveillance, the patient received a weekly blood PCR test for adenovirus; on day +25 it was noted he had reactivated adenovirus. He had been demonstrating overall clinical improvement, including declining hepatic transaminases and bilirubin, and reduced respiratory support requirements until day +39, when he developed fever with an increased need for respiratory support and rising transaminases. The respiratory viral panel showed that the patient was positive for adenovirus. Further workup also showed adenovirus PCR positive in stool and increase in quantitative adenoviremia, all consistent with disseminated adenoviral infection. The use of cidofovir was contraindicated in this patient due to renal toxicity.ALVR105 (Viralym-M), an allogeneic, off-the-shelf, multivirus-specific T-cell therapy (VST) that can target AdV, BKV, CMV, EBV, HHV-6, and JCV, was provided by AlloVir on a compassionate-use basis. A cell line that was HLA matched to the patient at 2 out of 8 HLA-A, HLA-B, HLA-DR, and HLA-DQ alleles was identified. After emergency IND approval, institutional review board approval, and family consent, one ALVR105 dose of 0.7 × 10 7 cells was infused on day +48. The dosage was calculated based on the patient's age, weight (8.5 kg), body surface area (0.35 m 2), and the dosing regimen used in a previous phase 2 trial. The patient developed fever and low blood pressure around 30 hours post-infusion, requiring an increase in his existing inotropic support and stress dose hydrocortisone. This was likely associated with underlying post-transplant complications, but a possible association with ALVR105 infusion could not be ruled out.The patient's viral load decreased substantially in the following weeks (Table 1). Concurrently, his liver enzymes, pulmonary secretions, and respiratory support requirements all improved. His respiratory secretions became negative for adenovirus PCR at day +28 post-infusion of ALVR105.At the time of writing, the patient was day +100 post-transplant (day +56 post-infusion of ALVR105), and his veno-occlusive disease had improved. Supplemental oxygen was no longer required, but volume-assured pressure was still in use, likely due to hepatosplenomegaly. The patient had detectable adenovirus viremia but below the threshold of quantitative measurement (<190 copies/ ml). The patient remains well-engrafted with evidence of persistent ALVR105 (Viralym-M) as illustrated in Table-2, but the % of Allovir cells are below our lab's 5% validation threshold. The patient's GVHD has resolved. MMF dosing was stopped on day + 31 from transplant, and the patient is receiving only cyclosporine and physiologic doses of hydrocortisone.Conclusion: In this infant with post allogeneic HCT disseminated adenovirus infection, ALVR105 appeared to be safe and was temporally associated with marked clinical improvement, suggesting VSTs may be of value in very young patients with adenovirus infection. This represents the first use of ALVR105 in an infant (< 1-year-old) patient. [Display omitted] DisclosuresMoon: Allovir: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure:Virus specific cell therapy, used against adenovirus infection in post-transplant setting.

Donor HLA Genotyping using Polymerase Chain Reaction- Sequence Specific Primers (PCR-SSP) as Method for Acquiring Donor Panel in Platelet Refractoriness

Background: Evaluation and identification of HLA antibodies in the recipient’s serum is of utmost importance prior to transplantation and transfusion. HLA typing is a steppingstone in proposing a donor panel. In order to obtain the HLA typing, Polymerase Chain Reaction-Sequence Specific Primers (PCR-SSP) can be performed.Materials and method: This is a preliminary study to determine HLA polymorphism by HLA genotyping in 43 blood donors. DNA from the samples was isolated using commercial kits according to the standard protocol. The DNA then was amplified using PCR-SSP methods and analyzed using the provided set in the kit.Results: This study found that the most frequent HLA-A alleles was HLA-A*24 (41.9%). For HLA-B alleles, the most common was HLA-B*15 (28%). Most frequent HLA-A-B haplotypes was HLA-A*24-B*15 (11.3%). The results from this study concurs with that of previous study. However, some alleles might vary due to difference in study population. Determining HLA-typing is of paramount importance in an ethnically diverse country such as Indonesia. In contrast to homogenous caucassian country, difference in ethnicity might cause platelet refractoriness due to incompatibility. HLA-typing would also guide the diagnostic workup and required treatment strategy for platelet refractoriness.Conclusion: From the HLA typing using PCR-SSP in blood donors in Jakarta, we found that the most frequent alleles were HLA-A*24 and HLA-B*15; and the most frequent haplotypes were HLA-A*24-B*15. This study should be upscaled to include larger population and ethnic groups to obtain complete profile of Indonesian population.Keywords: platelet refractoriness, HLA, donor, PCR-SSP, transfusion medicine

Identification of the novel allele, HLA-B*44:256, in an individual from West Bengal in Eastern India.

Next generation sequencing based HLA typing has led to the identification of a novel allele HLA-B*44:256. The novel allele HLA-B*44:256 differs from B*44:02:01:01 by eight nucleotides in exon 3.