Remestemcel-L

Pathogenesis of acute graft versus host disease: Acute graft versus host disease (aHvGD) occurs in recipients of allogenic stem cell transplantation and is characterized by differentiation and activation of alloreactive T lymphocytes. aGvHD is associated with tissue injury in various organs such as the liver, skin and intestinal mucosa. Acute GvHD can be summarized in a three-step process: conditioning phase, donor T-Cell activation, and cellular and inflammatory effector phase. The first phase involves the tissue damage induced by conditioning regimen (irradiation and chemotherapy) and production of inflammatory factors such as cytokines and adhesion molecules. The expression of MHC antigens and adhesion molecules is recognized by donor T cells. These donor T cells are activated in phase 2, resulting in subsequent proliferation, differentiation and secretion of cytokines including IL-2 and IFN-γ. These cytokines enhance T-cell expansion, induce cytotoxic T cells (CTL) and natural killer (NK) cell responses and facilitate the production of TNF-α and IL-1 by monocular phagocytes. Inflammatory cytokines promotes the production of inflammatory chemokines, thus recruits effector cells into target organs and initiates phase 3 of the disease. Phase 3 involves cascades of cell-mediated cytotoxicity and signalling of multiple inflammatory effectors, leading to amplification of local tissue injury and further promotion of an inflammatory response.

Mechanism of action of remestemcel-L: Human mesenchymal stem cells (hMSCs), or remestemcel-L, are derived from the bone marrow are capable of differentiation into cells derived from the mesoderm germ layer, such as osteocyte, adipocyte and chondrogenic cells. Once administered, they migrate to the site of inflammation to reduce the production of pro-inflammatory cytokines. It has been demonstrated that hMSCs secrete a wide range of bioactive molecules, such as growth factors, cytokines, and chemokines, that mediate regenerative and anti-apoptotic actions. Some molecules released by hMSCs include PGE2 and IL-10 for anti-inflammatory effects, or TGFβ1 and HLA-G5 for suppression of T cell proliferation. There is evidence that hMSCs interact with natural killers cells, monocytes, macrophages, effector T cells and regulatory T cells to shift their pro-inflammatory Th1 cytokine secretion profile to an anti-inflammatory Th2 cytokine profile. hMSCs also suppress NK cell proliferation and disrupts the migration, maturation, and antigen presentation of dendritic cells that differentiated from monocytes. In a mouse model of ischemia, remestemcel-L have been shown to stimulate the growth of new blood vessels, which is a process crucial to tissue repair, through secretion of factors such as VEGF. Overall, hMSCs exert immunomodulatory actions to inhibit inflammatory responses in aGvHD.