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A new player in graft-versus-host disease

Researchers have identified a long noncoding RNA whose function has shown to play a key role in graft-versus-host disease and organ transplant rejection.

Haematopoietic stem cell transplantation and graft-versus-host disease

Allogenic solid organ and haematopoietic stem cell transplantation (HSCT) are life-saving treatments for individuals with organ failure and high-risk malignancies, haematologic disorders and inherited metabolic disorders. Unfortunately, the efficacy of these treatments is limited by T cell-mediated alloimmune reactions that result in graft-versus-host disease (GVHD) and allograft organ rejection. These reactions can be mitigated by nonspecific immunosuppressive therapies that can have serious side effects. Researchers hope that with better understanding of T cell alloimmunity, more specific and better tolerated therapies can reduce undesirable effects.

Non-coding RNAs (ncRNAs) are important for gene expression and also control cellular processes. Long noncoding RNAs (lncRNAs) are a subset of ncRNAs that are >200 nucleotides long. They can both positively and negatively regulate gene expression in different ways. Dissimilarly to other ncRNA subsets, lncRNAs are produced in a tissue- and context-specific manner. This characteristic makes them tractable for antisense oligonucleotide-based medicines. The abundance of lncRNAs in T cells varies among T cell subsets and changes upon T cell activation. Nonetheless, the specific functions of most remain unknown. Furthermore, the abundance and function of lncRNAs in T cells after allogenic HSCT and solid organ transplantation is unclear.

An uncharacterised lncRNA

In this study, published in Science Translational Medicine, researchers performed RNA sequencing on T cells from healthy individuals and donor T cells from three different groups of HSCT recipients. These HSCT recipients specifically differed in their degree of MHC mismatch. The team also validated their findings in two independent cohorts.

They found that lncRNA differential expression was greatest in T cells after MHC-mismatched HSCT compared to T cells from MHC-matched and autologous HSCT. Among these lncRNAs, the team found Linc00402 – an uncharacterised lncRNA. They found that Linc00402 was conserved and exhibited an 88-fold increase in human T cells related to all other samples in the FANTOM5 database. Moreover, this RNA was also increased in donor T cells from patients who underwent allogenic cardiac transplantation.

The researchers also conducted experiments to see whether they observed the same response in the presence of another foreign invader – a viral infection. Interestingly, the team did not see an elevated level of the RNA in response to the virus. This strongly suggests that this dysregulation is only seen when T cells are put from one human being into another. To explore this further, the team conducted a series of experiments altering the expression of Linc00402. They found that Linc00402 plays a key role in T cells’ ability to respond to a threat by proliferating. The team hypothesised that its function is to help with cellular signalling following activation of T cells. 

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