“Three major events must occur to induce CD8+ T cell–mediated, tumor-protective immunity against syngeneic melanoma. First, the T-cell receptor must be triggered by a (or multiple) self antigen–derived peptide MHC class I complex (7–13). Therefore, this event depends entirely on appropriate antigen presentation, which is most efficiently provided by mature dendritic cells (14). Peripherally tolerant or “ignorant” self-reactive T-cell clones, once properly activated, may serve as tumor-specific effector T cells (15, 16).
Second, simultaneously with T-cell receptor triggering, a distinct second costimulatory signal must be delivered, mediated by IL-2, B7-1, or B7-2, which engage IL-2 receptors and CD28 on the surface of the T cell, respectively (17). A source of these cofactors for effective CD8+ T-cell stimulation can be provided by CD4+ T cells that release critical amounts of IL-2, or by mature dendritic cells that display an increased level of B7-1/B7-2 costimulatory molecules on their cell surfaces.
Third, inflammatory cytokines, including IL-1, IL-6, IL-12, and IFN-γ provide a third signal that acts directly on T cells (18), referred to as the “danger signal” (19, 20). This signal was found to optimally activate TH1 differentiation and lead to clonal expansion of T cells (18).”
Source: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=300854
On day 15 there inflammation around my axilla tumors.So all three signals were in place.
Source: The Maximum Propagation time was from ITOH ET AL.
Itoh, K; Platsoucas, CD; Balch, CMAutologous Tumor Specific Cytotoxic Lymphocytes in the Infiltrate of Human Metastatic Melanomas Activation by Interleukin 2 and Autologous Tumor Cells, and Involvement of the T Cell Receptor [published J . Exp. MED. The Rockefeller University Press. 1988 Oct 1; Vol 168 October 1988 1419-1441
Source: http://jem.rupress.org/cgi/reprint/168/4/1419.pdf
If you look at the graph, High dose was inoculated at the maximum CD8+ T cell propagation. This IL-2 addition promoted the induction of effector function. At about the same time the CTLA-4 was almost out of my system base on the half life. This is why I had no autoimmune response side effects.
IL-2 is commonly used as an adjuvant in immunotherapy protocols. In addition to playing a critical role in survival of CD8 T cells, when presented at high levels to antigen-activated CD8 cells, IL-2 can also promote the induction of effector functions, such as granzyme B (gzmB) via STAT5 signaling, thereby functioning as a costimulatory molecule and also as growth factor.
"IL-2 Regulates Perforin and Granzyme Gene Expression in CD8+ T Cells Independently of Its Effects on Survival and Proliferation1
Michelle L. Janas2, Penny Groves, Norbert Kienzle and Anne Kelso3 Cooperative Research Center for Vaccine Technology and Queensland Institute of Medical Research, Brisbane, Australia
“Granule-mediated cytotoxicity is one of the major mechanisms used by CD8+ T cells to eliminate harmful or foreign bodies, such as virus-infected cells, tumors, and allografts. After Ag recognition, activated CD8+ T cells release the contents of their cytotoxic granules into the extracellular space, where they are taken up by the target cell, and apoptosis is initiated (1). The cytotoxic granules contain a number of molecules, including the pore-forming protein, perforin, and serine proteases, known as granzymes. Perforin was originally thought to cause cell lysis by penetrating the target cell membrane (2), but recent work favors the theory that perforin functions by enabling the granzymes to escape from endosomes into the cytosol of the target cell (3, 4). Whatever its exact role, perforin is essential, because Ag-specific granule-mediated cytotoxicity is absent in perforin-deficient CD8+ T cells and NK cells (5).”Although the perforin and granzyme genes are known to be inducible, because a T cell must be activated before the cytolytic molecules are expressed at the mRNA or protein levels (13, 15), the signals responsible for regulating gene expression have yet to be identified. The exceptions are studies examining the role of the cytokine, IL-2. IL-2 has been shown to up-regulate perforin and granzymes A and B in human PBL (16), and binding sites for the IL-2-induced transcription factor, STAT-5, have been located in the perforin promoter region (17, 18)."
This is what I believed happen to me. I believe we need to investigate it. Since I am not Research Oncologist, I don’t know if anyone would take me serious. I went from 40 + nodulars in my lungs to NED and have been NED for two years.I believe we jump started my immune system.
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