Treatment of Pediatric Acute Graft-versus-Host Disease—Lessons from Primary Immunodeficiency?

Abstract

Allogeneic hematopoietic stem cell transplant (HSCT) is used to treat increasing numbers of malignant and non-malignant disorders. Despite significant advances in improved human leukocyte antigens-typing techniques, less toxic conditioning regimens and better supportive care, resulting in improved clinical outcomes, acute graft-versus-host disease (aGvHD) continues to be a major obstacle and, although it principally involves the skin, gastrointestinal tract, and liver, the thymus is also a primary target. An important aim following HSCT is to achieve complete and durable immunoreconstitution with a diverse T-cell receptor (TCR) repertoire to recognize a broad range of pathogens providing adequate long-term adaptive T-lymphocyte immunity, essential to reduce the risk of infection, disease relapse, and secondary malignancies. Reconstitution of adaptive T-lymphocyte immunity is a lengthy and complex process which requires a functioning and structurally intact thymus responsible for the production of new naïve T-lymphocytes with a broad TCR repertoire. Damage to the thymic microenvironment, secondary to aGvHD and the effect of corticosteroid treatment, disturbs normal signaling required for thymocyte development, resulting in impaired T-lymphopoiesis and reduced thymic export. Primary immunodeficiencies, in which failure of central or peripheral tolerance is a major feature, because of intrinsic defects in hematopoietic stem cells leading to abnormal T-lymphocyte development, or defects in thymic stroma, can give insights into critical processes important for recovery from aGvHD. Extracorporeal photopheresis is a potential alternative therapy for aGvHD, which acts in an immunomodulatory fashion, through the generation of regulatory T-lymphocytes (Tregs), alteration of cytokine patterns and modulation of dendritic cells. Promoting normal central and peripheral immune tolerance, with selective downregulation of immune stimulation, could reduce aGvHD, and enable a reduction in other immunosuppression, facilitating thymic recovery, restoration of normal T-lymphocyte ontogeny, and complete immunoreconstitution with improved clinical outcome as the ability to fight infections improves and risk of secondary malignancy or relapse diminishes.

Haematopoietic stem cell transplantation for inborn errors of immunity: 25‐year experience from University of Malaya Medical Centre, Malaysia

“…Neither of these patients experienced graft failure, and both are long‐term survivors. With regards to GVHD, we observed grades II–IV acute GvHD in 32% of our patients, comparable to reported rates of 28–56% in published series of similar paediatric cohorts …”

“…With regards to GVHD, we observed grades II-IV acute GvHD in 32% of our patients, comparable to reported rates of 28-56% in published series of similar paediatric cohorts. 16 In the earlier stages of our transplant program, HSCT for IEI were performed for patients who either had an HLA-matched sibling or were able to procure a matched unrelated cord blood unit. In the Malaysian setting, the probability of finding a MUD from the national donor registry is only 2-5%, due to a relatively small registry pool and ethnic heterogeneity.…”

Dynamics of recent thymic emigrants in pediatric recipients of allogeneic hematopoetic stem cell transplantation

“…different replicative history: CD31+ TREC-rich RTEs and CD31-TREC-poor peripherally expanded naïve CD4+ T cells [13][14][15] . In analogy to TRECs, the numbers of CD31+CD4+CD45+ T cells inversely correlate with ageing in healthy individuals and progressively decrease during immune senescence.…”

“…CD45RA and CD31 co-expressing CD4+ T cells were previously shown to express features of recent thymic emigrants (RTE), a group of de-novo generated thymic derived T cells characterized by a very high content of Tcell receptor excision circles (TREC). Their re-emergence in the peripheral blood after allo-HSCT is indicative for the recovery of thymic function after allo-HSCT-induced toxicity [13].…”

Comments on the article ‘Donor‐derived CD19‐targeted T cell infusion induces minimal residual disease‐negative remission in relapsed B‐cell acute lymphoblastic leukaemia with no response to donor lymphocyte infusions after haploidentical haematopoietic stem cell transplantation’

“…As is well known, corticosteroids can improve GVHD and cytokine release syndrome (Xu & Tang, ). However, short intensive corticosteroid courses, such as methylprednisolone, cause a profound reduction in naive T‐lymphocyte production (Flinn & Gennery, ), affecting CAR‐T cell efficacy. Perhaps, the molecular monitoring of CAR‐T copies should become a routine surveillance in patients.…”