Unique features and clinical importance of acute alloreactive immune responses

Abstract

Allogeneic stem cell transplantation (allo-SCT) can cure some patients with hematopoietic malignancy, but this relies on the development of a donor T cell alloreactive immune response. T cell activity in the first 2 weeks after allo-SCT is crucial in determining outcome, despite the clinical effects of the early alloreactive immune response often not appearing until later. However, the effect of the allogeneic environment on T cells is difficult to study at this time point due to the effects of profound lymphopenia. We approached this problem by comparing T cells at week 2 after allograft to T cells from autograft patients. Allograft T cells were present in small numbers but displayed intense proliferation with spontaneous cytokine production. Oligoclonal expansions at week 2 came to represent a substantial fraction of the established T cell pool and were recruited into tissues affected by graft-versus-host disease. Transcriptional analysis uncovered a range of potential targets for immune manipulation, including OX40L, TWEAK, and CD70. These findings reveal that recognition of alloantigen drives naive T cells toward a unique phenotype. Moreover, they demonstrate that early clonal T cell responses are recruited to sites of subsequent tissue damage and provide a range of targets for potential therapeutic immunomodulation.

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

“…[173][174][175][176][177][178][179][180][181] Of note, performing these ex vivo experiments with human cells generally involves allogeneic settings, since DCs or T cells derived from healthy individuals are typically not HLA-matched to human cancer cell lines. 156,[182][183][184][185][186][187][188][189][190] Thus, proper controls are needed for ruling out allogeneic graftversus-host immune reactions as confounding factors. 191 Moreover, ex vivo experiments cannot substitute for vaccination or abscopal tests in vivo, as some compounds are capable of eliciting all the hallmarks of ICD when administered to cancer cells, and yet those cells are unable to initiate anticancer immunity.…”

Genetic T-cell receptor diversity at 1 year following allogeneic hematopoietic stem cell transplantation

“…derived from latent viruses present in the recipient) drive a cytokine-mediated expansion of the mature donor T cells infused with the graft (5,6). This pathway, which is independent of the thymus, result in a skewed repertoire closely associated with infections and GVHD (7)(8)(9). By contrast, de novo maturation of naïve T cells derived from lymphoid precursors of the donor and selected in the thymus by the self-HLA molecules presenting self-peptides will restore a broad and fully responsive repertoire.…”

Rapid Manufacturing of Highly Cytotoxic Clinical-Grade SARS-CoV-2-specific T Cell Products Covering SARS-CoV-2 and Its Variants for Adoptive T Cell Therapy

“…One of the most dreaded side effects of the administration of T cell products is the development of Graft-versus-Host Disease (GvHD) triggered by alloreactive T cells in the product. The presence of naive T cells in T cell products precipitates the risk of GvHD, since naive T cells have a typically broader T cell receptor (TCR) repertoire and, therefore, a higher alloreactivity potential than memory T cell fractions ( Nikolich-Zugich et al, 2004 ; Inman et al, 2018 ). In a single center dose escalation study in Spain, CD45RA-depleted, unselected memory T cells from COVID-19 convalescent donors were given at increasing doses of 1 × 10 5 , 5 × 10 5 , and 1 × 10 6 memory T cells/kg body weight to hospitalized COVID-19 patients at risk for a severe course ( Perez-Martinez et al, 2021 ; Pérez-Martínez et al, 2021 ).…”