Apoptosis, or programmed cell death, is a natural and critical process in tissue and organ maintenance that occurs when a cell is damaged beyond repair, infected with a virus or undergoing other stressful conditions. Apoptosis involves a series of biochemical events leading to changes in cell morphology and ultimately, cell death. Immediate removal of the dying cell is performed by antigen presenting cells, macrophages and dendritic cells. The primary function of dendritic cells is phagocytosis, or the capturing and transportation of antigens to draining lymphoid tissues. Immature dendritic cells are capable of large-scale phagocytosis of apoptotic cells. As third-party in vivo and in vitro studies have demonstrated, injection of a high volume of densely concentrated apoptotic cells activates dendritic cells, causing them to migrate to the lymphoid tissues where they interact with T-cells and B-cells, which are lymphocytes involved in the regulation of the immune system, remove the apoptotic cells and suppress inflammation, thereby inducing immunotolerance, as opposed to general immunosuppression, which would otherwise make the patient more susceptible to infection and other immunological challenges. Using this inherent immune pathway, we believe that we can use Allocetra to shape the patient’s innate immune response to the disease, leading to a decrease in unwanted immune response. During the apoptotic cell removal process, several therapeutic responses are induced, such as inflammation suppression, modulation of macrophage-directed deletion of invading pathogens and regulation of immune responses. These responses are the target of Allocetra. We believe that Allocetra can specifically target the immune response responsible for GvHD and induce immunotolerance of the patient’s cells to the graft (or transplanted cells) without simultaneously diminishing the general immune capabilities of the patient or compromising the patient’s ability to respond to immunological challenges.
Dendritic cells (DCs) are the most potent antigen presenting cells. Their primary function is to capture antigens in the periphery and transport them to draining lymphatics, where they engage T cells and induce deletional, immune unresponsiveness (anergy), tolerance or T cell activation. Immature DCs are capable of large-scale phagocytosis of apoptotic cells. DCs are also known to capture and cross-present antigens from apoptotic cells, leading to a skewing of the cytokine milieu, including an increase of transforming growth factor (TGF ) and a decrease of interleukin-12 (IL-12) release. Ingestion and even the presence of a dying cell may shut down a potentially inflammatory APC, converting it to be in a state of tolerization. Another mechanism for tolerance induction by DCs is triggering, or differentiation, of regulatory T cells. Due to the fact that DCs are part of the innate immune system and are unable to distinguish between self- and donor-derived antigen, input from other cells such as non-classic T-cells or CD4+ helper cells is required for their activation, or ‘tolerization.’
In vivo and in vitro studies have demonstrated that an effective and physiological way to tolerize DCs is via interaction with apoptotic cells. Overall, the apoptotic cells removal process has been shown to induce several changes and functional activities in the engulfing APC such as inflammation suppression, modulation of macrophages-directed deletion of invading pathogens and regulation of immune responses.
We believe that our Allocetra cells invoke the following mechanisms: inhibition of pro-inflammatory cytokine production, promotion of anti-inflammatory cytokines production, decreased stimulation of T-cell responses, deletion of CD8 T-effector cells, and induction of regulatory T-cells. Apoptotic cell infusion represents a physiological way to induce tolerance to the patient effector cells that lead to decrease in the immune response.