HLA Matching at the Eplet Level Protects Against Chronic Lung Allograft Dysfunction.

Donor selection in lung transplantation (LTx) is historically based upon clinical urgency, ABO compatibility, and donor size. HLA matching is not routinely considered; however, the presence or later development of anti-HLA antibodies is associated with poorer outcomes, particularly chronic lung allograft dysfunction (CLAD). Using eplet mismatches, we aimed to determine whether donor/recipient HLA incompatibility was a significant predictor of CLAD. One hundred seventy-five LTx undertaken at the Alfred Hospital between 2008 and 2012 met criteria. Post-LTx monitoring was continued for at least 12 months, or until patient death. HLA typing was performed by sequence-based typing and Luminex sequence-specific oligonucleotide. Using HLAMatchmaker, eplet mismatches between each donor/recipient pairing were analyzed and correlated against incidences of CLAD. HLA-DRB1/3/4/5+DQA/B eplet mismatch was a significant predictor of CLAD (hazard ratio [HR] 3.77, 95% confidence interval [CI]: 1.71-8.29 p < 0.001). When bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) were analyzed independently, HLA-DRB1/3/4/5 + DQA/B eplet mismatch was shown to significantly predict RAS (HR 8.3, 95% CI: 2.46-27.97 p < 0.001) but not BOS (HR 1.92, 95% CI: 0.64-5.72, p = 0.237). HLA-A/B eplet mismatch was shown not to be a significant predictor when analyzed independently but did provide additional stratification of results. This study illustrates the importance of epitope immunogenicity in defining donor-recipient immune compatibility in LTx.

Neurodevelopmental outcome at seven years in term, acidotic newborns.

The objective was to follow up a cohort of acidotic full-term infants with or without hypoxic ischemic encephalopathy (HIE) and determine if at 7 years they displayed any neurodevelopmental delays. Children (n=44) were divided according to those with mild (n=25) or severe (n=19) acidosis and were then further subdivided into those with or without HIE. Participants were assessed using the Wechsler Intelligence Scale for Children (WISC-IVUK) and Achenbach Child Behaviour Checklist (CBCL). No differences in WISC-IVUK scores in children without HIE irrespective of the cord pH values were found. Children with HIE grade I scored significantly higher in perceptual reasoning than those with grade III (p<0.01). CBCL scores revealed no differences between groups. Findings suggest evidence of impairment at school-age that correlates with the degree of encephalopathy. Acidosis without the presence of clinical encephalopathy was associated with normal outcome.

Long-term follow-up of a pilot study using a chemotherapy-alone protocol for killer Ig-like receptor-ligand-mismatched haploidentical haematopoietic SCT.

Advanced haematological malignancies are incurable without allogeneic haematopoietic SCT (HSCT). Many patients do not have a human leukocyte Ag (HLA)-matched donor; hence, haploidentical HSCT has been explored for some 20 years. Previous poor outcomes have improved recently with modifications, including the use of killer Ig-like receptor (KIR)-ligand-mismatched donors and highly T-cell-depleted megadose CD34+ stem cell infusions. Haploidentical HSCT was undertaken in 10 patients with heavily pretreated and advanced myeloid malignancies. Patient/donor pairs were KIR-ligand mismatched (GVL direction). Conditioning regimen was ATG, melphalan, fludarabine and thiotepa. G-CSF-mobilized PBSCs were CD34+ cell selected. No post transplant immunosuppression was given. Two patients died early; all others had sustained engraftment. Natural killer cell recovery, often to supranormal levels, occurred early, whereas CD4+ T-cell recovery was delayed. Acute GVHD occurred in three of eight (30%) patients, and chronic GVHD occurred in three of six (50%) evaluable patients. No infections with Candida or Aspergillus developed in seven patients receiving caspofungin prophylaxis. Three of 10 (30%) patients were alive and disease free at 10.1, 6 and 5.4 years post transplant (Karnovsky scores of 100%). In this heavily pretreated cohort with very advanced myeloid malignancies, KIR-ligand-mismatched haploidentical HSCT cured a significant proportion of patients.

Donor methylenetetrahydrofolate reductase genotype is associated with graft-versus-host disease in hematopoietic stem cell transplant patients treated with methotrexate.

Methotrexate (MTX), used as a graft-versus-host disease (GvHD) prophylactic agent in hematopoietic stem cell transplantation (HSCT), exerts its effect via folate cycle inhibition. A critical enzyme involved in folate metabolism is 5,10-methylenetetrahydrofolate reductase (MTHFR). We examined the association of a single nucleotide polymorphism (SNP) at position 677 in the MTHFR gene on GvHD outcomes in allogeneic HSCT patients administered MTX. MTHFR genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on 193 HSCT patients and donors. A total of 140 patients were transplanted with an HLA-matched related donor and 53 with an unrelated donor. GvHD outcomes were compared between genotypes by univariate and multivariate analysis. The combined donor 677CT and TT genotypes were associated with a decreased incidence of GvHD (acute and chronic combined) in HSCT recipients with an HLA-matched related donor (75% at 1 year in the CT and TT group compared with 91% in the wild type CC group, P=0.01), increased time to onset of first GvHD (P=0.001) and time to first GvHD treated with systemic therapy (P=0.022). Unrelated donor MTHFR genotype was not associated with outcome parameters and no associations of recipient genotype in either related or unrelated donor cohorts were observed.

HLA-B27 expression and reactive arthritis susceptibility in two patient cohorts infected with Salmonella Typhimurium.

BACKGROUND: Reactive arthritis (ReA) is an inflammatory arthritis triggered by certain gastrointestinal and genitourinary infections. Single source outbreaks of triggering infections provide an opportunity to elucidate host susceptibility factors in this disease. AIM: To determine the role of Major Histocompatibility Complex (MHC) Class I alleles in ReA susceptibility after two large single source outbreaks of Salmonella Typhimurium gastroenteritis. METHODS: A questionnaire screening for features of ReA and a request for HLA class I typing were sent to all patients affected by two single source outbreaks of S. Typhimurium gastroenteritis. Individuals with arthritis of recent onset were interviewed, examined and diagnostic criteria for ReA applied. RESULTS: Nineteen cases of reactive arthritis, 11 female, were diagnosed in the 424 respondents with S. Typhimurium gastroenteritis from both outbreaks. Clinical features of the arthritis were similar to those described after other large single source outbreaks of Salmonella infection. HLA-B27 was expressed by only two of the 19 ReA patients and therefore did not predict susceptibility to this form of arthritis. Caucasians were, however, more likely to develop reactive arthritis than Asians. CONCLUSIONS: In this study, susceptibility to ReA was not increased in HLA-B27 positive individuals or males but was greater in those of Caucasian descent.