The immune system has evolved to respond not only to pathogens, but also to signals released from dying cells. These signals are generated by molecules call Alarmins.
In response to infection and/or tissue injury, cells of the host innate immune system rapidly produce a variety of structurally distinct mediators that not only function as potent effectors of innate defense but also act to alarm the immune system by promoting the recruitment and activation of host leukocytes through interaction with distinct receptors. One of these Alarmins is the High mobility group box 1 (HMGB1).
(HMGB1) is a DNA-binding nuclear protein, released actively following cytokine stimulation as well as passively during cell death; it is the prototypic damage-associated molecular pattern (DAMP) molecule and has been implicated in several inflammatory disorders, but our case, it is the molecule that sends the red flag up to the immune system, stating there is a problem.
This Alarmin (HMGB1) is capable of activating antigen-presenting cells (APCs) and enhancing the development of antigen-specific immune responses.
The interaction of high mobility group box 1 protein (HMGB1) released from dying tumor cells with Toll-like receptor 4 (TLR) on dendritic cell was required for the crosspresentation of tumor antigens and the promotion of tumor specific cytotoxic T-cell responses.
Under stress conditions, such as injury or infection, HMGB1 is released and promotes inflammation. (Danger Signal) HMGB1 is passively released by Death of cells or tissues through injury or disease (necrotic) but not apoptotic death. Disintegration of cells into membrane-bound particles that are then eliminated by phagocytosis or by shedding of normal cells and actively secreted by a variety of activated immune and non-immune cells.
Through the TLR4, HMGB1 activates NFκB inducing a wide range of host changes that include activation of the innate immune system (neutrophils, NK cells, dendritic cells) and secretion of proinflammatory cytokines and mediators.
There is growing evidence that the relationship between the inflammatory process and cancer is complex. Our understanding of this relationship as it relates to Danger Signal development and or progression of malignancy is still limited. Further evaluation in patients is clearly needed if we are to truly understand whether there is therapeutic potential in targeting Pro-inflammation, “The Danger Signal”.
HMGB1 as a DAMP released into the tumor microenvironment plays a central role in the recruitment and activation of innate immune cells.
This emergent understanding of the danger signals also called alarmins or damage associated molecular patterns (DAMPs) is fueling new research that may be beneficial to finding a cure.
This ability of dendritic cells to recreate the environment associated with necrosis via the regulated secretion of HMGB1 represents a successful evolutionary strategy and places HMGB1 at the crossroads between innate and adaptive immunity.
Once T-cells are activated, RAGE and HMGB1 are upregulated during cellular activation, consistent with a role of the RAGE axis in pro-inflammatory immune responses.
So how do we cause tumor cells to die? We don’t need to kill them all at once, that would be nice, and we need to a portion so that HMGB1 is secreted. Or do we inject a mixture of naturally occurring Cytokines that act as the pro-inflammatory cytokines, (the Danger Signal)?
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A little known company is just doing that. The company is IRX Therapeutics.
Irx Therapeutics, Inc
2350 Broadhollow Road
Farmingdale, NY 11735-1006
Dr. John W Hadden founded the company in 1994 and holds the patent on the cytokine mixture called IRX-2.
The cytokine components of IRX-2 (includes IL-1, IL-2, IL-6, IL-8, IFN-γ, TNF-α, G-CSF and GM-CSF) are known to promote both T lymphocyte and dendritic cell development and function and monocyte function.
I believe the natural cytokine mixture (NCM). The NCM includes 1L1, IL2, IL6, IL8, IL10, IL12, .delta.IFN, TNF.alpha. and G- and GM-CSF could play a pivotal role in activation of the T-cells (CD4+ and CD8+). This mixture that is in the patent (20030206885) is what I would call the Proinflammatory Cytokines, the “Danger Signal”.
The natural cytokine mixture is missing MCP-1, MIP-1 alpha and beta which is very important to attract immune cells to the tumor’s microenvironment.
CCL3/MIP-1 alpha acts as a chemoattractant to a variety of cells including monocytes, T cells, Dendritic cells, B cells and eosinophils
CCL4/MIP-1 beta is expressed primarily by T cells, B cells, and monocytes after antigen or mitogen stimulation. The functional receptor for MIP-1 beta has been identified as CCR5.
CCL4, also known as macrophage inflammatory protein 1 beta (MIP1β)
is a 7.8 kDa β chemokine that is secreted at sites of inflammation by activated leukocytes, lymphocytes, vascular endothelial cells.
CCL4 attracts a variety of immune cells to sites of microbial infection as well as to other pathologic inflammation.
Monocyte chemoattractant protein-1 (MCP-1) is important in attracting monocytes to sites of inflammation. Besides induction of monocyte recruitment, MCP-1 can also affect chemotactic response of endothelial cells.
I speculate by combining Radiation, Chemotherapy, Ipilimumab, IRX-2, and IL-2 in a systematic way, we can induce an immune response against Melanoma and win most of the Battles. Let the war games begin. Who will take on this challenge and be the first to CURE Melanoma? We shall see.
A clue: This is from a patient that is receiving Ipilimumab (Yervoy)
“The Dr. says it's possible the swelling is caused by the tumors starting to respond. My back and leg tumors did become inflamed before they receded, so it's possible the same is happening in the brain. I could also be having a delayed reaction.”
From a paper of Dr. Meenhard Herlyn.
Inflammation is the key to the Danger Signal which can be produced by dying Tumor cells or Ipilimumab differentiating T-cells into Th-17 Phenotype or by injecting a pro-flammatory cytokine mixture. Let the War on Melanoma Begin!!!!!
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B
