PMC:6141714 / 21277-24627
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/6141714","sourcedb":"PMC","sourceid":"6141714","source_url":"https://www.ncbi.nlm.nih.gov/pmc/6141714","text":"While the development of acute GvHD is related to the activation of alloreactive T lymphocytes of the graft, the development of chronic GvHD involves both alloreactive and autoreactive mechanisms (169). The immune response of acute GvHD occurs in two phases, one afferent and one efferent. In the afferent phase, CD4+ and CD8+ T cells react to the host's class I and II alloantigens present on the surface of antigen-presenting cells (APCs) (166). This phase starts when the conditioning regimen initiates an immune response due to the damage to host tissues, such as the intestinal mucosa and liver, which results in the induction of cytokine secretion, especially IL-1 and tumor necrosis TNF-α (170). After HSCT, donor's T cells are stimulated by the IL-1 and by the costimulatory signals present, producing IL-2. Under the influence of IL-2, CD4+ and CD8+ T cells clonally expand and differentiate into effector cells, which induce the graft response against the host (170). These effector cells are activated by costimulatory molecules and proinflammatory cytokines such as IFN-γ and IL-12, giving rise to T helper 1 (Th1) effector cells, which direct even more the graft response against the host (171). In the efferent phase of GvHD, activated T cells secrete a storm of cytokines such as IL-2, IL-4, IL-3, and IFN-γ. These mediators recruit and activate effector cells, including additional lymphocytes, macrophages, and natural killer (NK) cells, which attack both donor and host tissues (170). The mechanisms of action of the hMSCs administered included effects in the proliferation and differentiation of immune cells and changes in the expression pattern of growth factors, cytokines, enzymes, prostaglandins and surface receptors and ligands. While some studies reported an increase in the levels of growth factors such as HGF (34, 72), IGF-1 (34), VEGF (34, 72), bFGF (34, 71), TGF-β (39, 41), activin A (72), and NGF (71), others demonstrated an increase in the levels of the prostaglandin E2 (34, 41, 72) (PGE2) and the enzymes IDO (39, 72), Cox-2 (72), and granzyme B (71). Generally, an increase in levels of immunomodulatory cytokines such as IL-10 (36, 58, 71) and IL-23 (71) and a decrease in the levels of pro-inflammatory cytokines such as TNF-α (35, 36, 55, 64), IFN-γ (36, 41, 55, 64), IL-1β (64), IL-2 (36), IL-8 (71), CCL2 (71), CXCL9 (71), and CXCL10 (71) following treatment with hMSCs was observed by most studies. In addition, some studies reported an increase in the serum levels of IL-6 (50, 72), a cytokine with both pro-inflammatory and anti-inflammatory properties, after administration of hMSCs while another study reported an increase in the levels of GM-CSF (71), a cytokine usually employed to stimulate the production of leukocytes in order to prevent neutropenia after chemotherapy. A change in the expression of cell surface receptors and ligands following the administration of hMSCs for the treatment of GvHD was also demonstrated by some studies. For instance, a decrease in the expression of PPAR-γ (51), IL-2 (49, 66, 71), and TNF-α (66, 71) receptors and in the CD40 ligand (71) (CD40L) was observed in some articles while an increase in the expression of the protein receptor CTLA-4 (58) and NRP-1 (72) and in the PD-ligand 1 (72) (PD-L1) and CCR2 (71) ligand (CCL7) was demonstrated by other 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