No abstract

To the Editor Hyperhaemolysis syndrome (HHS) is a severe post-transfusion complication that can develop rapidly and cause life-threatening anaemia and death unless recognised and treated promptly. 1,2 It is mostly, but not exclusively, seen in sickle cell patients, often after multiple previous transfusions. In patients with previous history of hyperhaemolysis, further transfusions should be avoided, but if essential, transfusion should be administered with prophylactic intravenous immunoglobulins (IVIG) and steroids, antigen-negative red cells if there are known alloantibodies, matching the patient's full extended phenotype if feasible. [3][4][5] However, as this case demonstrates, prophylaxis with standard first line therapy and compatible phenotyped blood may not be sufficient to prevent further episodes of HHS.HHS is characterised by the destruction of transfused and autologous red cells resulting in a fall in haemoglobin (Hb) to below pretransfusion levels, and by reticulocytopenia. Typically, in the acute type of HHS, no new alloantibodies are detected, other than preexisting antibodies, and in half the cases the DAT remains negative. 6,7 The pathogenesis of HHS remains unclear, but is associated with systemic symptoms of inflammation and extreme hyperferritinaemia that are indicative of macrophage activation. 2,8,9 Histopathological studies in patients with HHS have demonstrated the presence of widespread macrophage erythrophagocytosis in the liver, spleen and bone marrow, suggesting that macrophage activation and direct erythrophagocytosis is an important mechanism of red blood cell destruction. 10

T-cell responses to minor histocompatibility antigens (mHAs) mediate graft versus leukemia (GvL) effects and graft versus host disease (GvHD) in allogeneic hematopoietic cell transplant (alloHCT). Therapies that boost T cell responses improve alloHCT efficacy, but are limited by concurrent increases in incidence and severity of GvHD. mHAs with expression restricted to hematopoietic tissue (GvL mHAs) are attractive targets for driving GvL without causing GvHD. Prior work to identify mHAs has focused on a small set of mHAs or population-level SNP association studies. We report the discovery of a large set of novel GvL mHAs based on predicted immunogenicity, tissue expression, and degree of sharing among donor-recipient pairs (DRPs) in the DISCOVeRY-BMT dataset of 3231 alloHCT DRPs. Total number of predicted mHAs varied by HLA allele, and total number and number of each class of mHA significantly differed by recipient genomic ancestry group. From the pool of predicted mHAs, we identified the smallest sets of GvL mHAs needed to cover 100% of DRPs with a given HLA allele. We used mass spectrometry to search for high population frequency mHAs for three common HLA alleles. We validated 24 novel predicted GvL mHAs that cumulatively are found within 98.8%, 60.7%, and 78.9% of DRPs within DISCOVeRY-BMT that express HLA-A*02:01, HLA-B*35:01, and HLA-C*07:02 respectively. We confirmed immunogenicity of an example novel mHA via T cell coculture with peptide-pulsed dendritic cells. This work demonstrates that identification of shared mHAs is a feasible and promising technique for expanding mHA-targeting immunotherapeutics.

A 60 year old woman reports sudden dizziness when she arises from bed. She feels nauseous and had been vomiting. She recently had a severe cold. Her vomiting has settled, but she is dizzy on turning her head to the right. She is frightened to leave her house.