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Type I diabetes mellitus (T1DM) is an organ-specific autoimmune disorder affecting the insulin-producing pancreatic cells. T1DM genetic association studies have so far revealed the involvement of more than 40 loci, with particularly strong associations for the human leucocyte antigens (HLA). Further to the well-established HLA class II associations, the immunomodulatory elements in the telomeric major histocompatibility complex locus, specifically nonclassical HLA class I, were also associated with T1DM, either in conferring susceptibility or by contributing to the overall pathogenesis. This study investigates the involvement of a 14-bp deletion polymorphism ( rs371194629) at the 3′ untranslated region of HLA-G in the context of T1DM and age of onset. The frequency of the polymorphism was determined in unrelated T1DM Cypriot patients and findings that emerge from this study show a strong association between the HLA-G 14-bp polymorphism and T1DM with respect to the age of onset. Specifically, the deletion/deletion ( DEL/DEL) genotype was found to be associated with an early age of onset ( P = 0.001), while the presence of the insertion allele (INS) was associated to a later age of onset ( P = 0.0001), portraying a possible dominant effect over the deletion allele, a role in delaying disease onset and an overall involvement of HLA-G in the pathogenesis of type I diabetes mellitus. [ABSTRACT FROM AUTHOR]

Human leucocyte antigen ( HLA) compatibility is the main factor determining the occurrence of graft- vs-host disease (GVHD) in patients. It has also been shown that minor histocompatibility antigen differences as well as genetic polymorphisms that are not sequenced by standard methodology for HLA typing can play a role. We used mixed lymphocyte cultures (MLCs) as a functional cellular test and investigated gene expression changes driven by HLA incompatibility in an effort to better understand the mechanisms involved in the disease. Gene expression profile of HLA matched and HLA mismatched MLC identified differentially regulated genes and pathways. We found that a great number of genes related to immune function were differentially regulated; these genes were also found to be associated with GVHD and graft rejection. The majority of differentially regulated genes were interferon-gamma ( IFNγ)-inducible genes and IFNγ neutralisation in MLCs abrogated their induction. The microRNA-155, a recently identified target for acute GVHD (aGVHD), was also found to be significantly induced in HLA mismatched MLC but not in the matched setting and its induction was not diminished by blocking IFNγ. In this proof-of-principle study we show gene expression changes in mismatched MLC that represent alloreactive responses, correlate with markers involved in GVHD and can potentially be useful in the study of the biological processes involved in this disease. [ABSTRACT FROM AUTHOR]

Inherited deficiencies of UDP-galactose 4-epimerase (GALE) havebeen associated with two distinct phenotypes. The vast majority of North American patients are clinically asymptomatic, are identified through newborn screening programmes for classical galactosaemia, and are of African-American descent. At least two symptomatic patients have been reported, one Pakistani and the other Asian Muslim, both with severe complications in the neonatal period and subsequent mental retardation. Through newborn screening, we have identified a GALE-deficient patient who is of mixed Pakistani/caucasian ancestry. He was clinically well in the neonatal period on a lactose-containing diet, and biochemical studies, including urine reducing sugars and galactitol, were consistent with a diagnosis of peripheral GALE deficiency. Although early developmental milestones were met normally, he now shows significant developmental delays in both motor and language skills. Mutational analysis revealed this patient to be a compound heterozygote at the GALE locus, with mutations N34S and L183P identified in the patient and confirmed in the parents. This report represents the first characterization of specific mutations ina GALE-deficient patient in conjunction with biochemical and clinical pheno-type, and facilitates further studies of the GALE enzyme and its role in the different clinical forms of epimerase-deficiency galactosaemia. [ABSTRACT FROM AUTHOR]

Advances in immunotherapy with T cells armed with chimeric antigen receptors (CAR-Ts), opened up new horizons for the treatment of B-cell lymphoid malignancies. However, the lack of appropriate targetable antigens on the malignant myeloid cell deprives patients with refractory acute myeloid leukaemia of effective CAR-T therapies. Although non-engineered T cells targeting multiple leukaemia-associated antigens [i.e. leukaemia-specific T cells (Leuk-STs)] represent an alternative approach, the prerequisite challenge to obtain high numbers of dendritic cells (DCs) for large-scale Leuk-ST generation, limits their clinical implementation. We explored the feasibility of generating bivalent-Leuk-STs directed against Wilms tumour 1 (WT1) and preferentially expressed antigen in melanoma (PRAME) from umbilical cord blood units (UCBUs) disqualified for allogeneic haematopoietic stem cell transplantation. By repurposing non-transplantable UCBUs and optimising culture conditions, we consistently produced at clinical scale, both cluster of differentiation (CD)34 + cell-derived myeloid DCs and subsequently polyclonal bivalent-Leuk-STs. Those bivalent-Leuk-STs contained CD8 + and CD4 + T cell subsets predominantly of effector memory phenotype and presented high specificity and cytotoxicity against both WT1 and PRAME. In the present study, we provide a paradigm of circular economy by repurposing unusable UCBUs and a platform for future banking of Leuk-STs, as a 'third-party', 'off-the-shelf' T-cell product for the treatment of acute leukaemias., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)