TNF-a induces the synthesis of both IL-1 and IL-6 in macrophages. In contrast, IL-10, which is also synthesized by macrophages, inhibits the synthesis of TNF-a, IL-1 and IL-6. Both IFN-g and TNF-a can activate macrophages, which subsequently synthesize TNF-a and IL-1. What I am trying to elude to is that depending on the microenvironment which contains many cytokines, the pattern of cytokines matters whether the macrophages are activated or not.
This does not take into account the suppressiveness of the Tumor’s activity. Melanoma tumors can secrete TGF-b and IL-10 and other suppressive molecules. These suppressive cytokines (IL-10) can block the activation of the tumor associated macrophages (TAMs) which in turn inhibits the secretion of other cytokines and chemoattractants into the Tumor’s microenvironment. This inhibition suppresses the “Danger Signal” needed to alarm the immune system of foreign invaders (Tumor cells).
Th1 cells promote macrophage activation by producing IL-2 and IFN-g. What if the Th1 cells are not producing enough or there are many Tregs in the tumor’s microenvironment recruited by the tumors themselves? The Tregs, Th1 and the CD8+ T-cells are all competing for the IL-2 for survival. There could be a shortage of IL-2 to satisfy all the cells leading to a less than robust response. It has been greatly accepted that macrophage activation by IL-2 is essential for tumor regression. et al Masztalerz
So administration of HD IL-2 during the peak propagation of the (ALC) Absolute Lymphocyte Count (7 weeks or 49 days) may be synergetic to Yervoy.
“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
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