Abstract
Since their discovery CD4+FOXP3+ regulatory T cells (Tregs) represented a promising tool to induce tolerance in allogeneic hematopoietic cell transplantation. Preclinical models proved that adoptive transfer of Tregs or the use of compounds that can favor their function in vivo are effective for prevention and treatment of graft-vs.-host disease (GvHD). Following these findings, Treg-based therapies have been employed in clinical trials. Adoptive immunotherapy with Tregs effectively prevents GvHD induced by alloreactive T cells in the setting of one HLA haplotype mismatched hematopoietic transplantation. The absence of post transplant pharmacologic immunosuppression unleashes T-cell mediated graft-vs.-tumor (GvT) effect, which results in an unprecedented, almost complete control of leukemia relapse in this setting. In the present review, we will report preclinical studies and clinical trials that demonstrate Treg ability to promote donor engraftment, protect from GvHD and improve GvT effect. We will also discuss new strategies to further enhance in vivo efficacy of Treg-based therapies.
Highlights
CD4+FOXP3+ regulatory T cells (Tregs) are capable of suppressing the function of conventional CD4+ and CD8+ T cells (Tcons), B cells, natural killer (NK) cells and antigen presenting cells (APCs)
Tregs develop in the thymus with a T cell receptor (TCR) repertoire that overlaps to some extent with that of Tcons [9,10,11,12]
When donor CD4+CD25+ Tregs were co-infused at a 1:1 ratio with Tcons more than 70% of mice were protected from lethal acute graft-vs.-host disease (GvHD)
Summary
CD4+FOXP3+ regulatory T cells (Tregs) are capable of suppressing the function of conventional CD4+ and CD8+ T cells (Tcons), B cells, NK cells and antigen presenting cells (APCs). They maintain tolerance to self and prevent autoimmune diseases, control excessive immune responses to allergens and pathogens, help maintain a balance with commensal microbial flora and the maternal tolerance to fetus. Donor alloreactive T cells recognize recipient alloantigens, eliminate malignant cells [graft-vs.-tumor (GvT) effect] and can prevent relapse They attack host normal tissues (mainly skin, gut and liver), causing graft-vs.-host disease (GvHD), that is a major cause of non-relapse mortality (NRM). Tregs contribute to induction and maintenance of tolerance to alloantigens, facilitating engraftment and preventing the development of GvHD [54,55,56]
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