Thanks to Dr. Megan Levings for taking time out of her busy schedule to email me her research paper on Tregs cells. In my research, I have come to the conclusion that that major barrier to initiating an immune response is over coming the Treg suppression. Remember I said “BLAME IT ON THE TREGS”, well most of the research finding are supporting this piece of the Melanoma Puzzle.
“T-regulatory cells (Tregs) have a fundamental role in the establishment and maintenance of peripheral tolerance. There is now compelling evidence that deficits in the numbers and/or function of different types of Tregs can lead to autoimmunity, allergy, and graft
rejection, whereas an over-abundance of Tregs can inhibit anti-tumor and anti-pathogen immunity.”
“Several different types of Tregs exist in humans, including specialized subsets of CD4+, CD8+, double negative CD3+ CD4-CD8-, alpha /gamma T cells, and natural killer T (NKT) cells. While it is likely that these different types of Tregs work together in a network to maintain immune homeostasis, the majority of current research is focused on defining the normal function of CD4+ Tregs, because these cells mediate dominant, long-lasting, and transferable tolerance in experimental models.”
Levings and colleagues want to harness the Tregs to develop adoptive cellular therapy protocols that would be used in autoimmunity and inflammation. So they wanted to grow the population of Tregs. We on the other hand want to deplete/suppress them, to push the balance towards an immune response.
The Tregs constitute only 1-2 % of the peripheral CD4+ T cells in humans, but is enough to keep the immune system in check. In in-vitro culture conditions, they can expand rapidly when stimulated with an antigen. If you throw Il-2 into the mix, It can increase the cell population by 5-6 fold. This means that the Treg population when activated and Il-2 is secreted or added like (HD IL-2), is now at 10 to 12 % of the population. This can quickly shut down the immune response. So the Takeaway is that one must plan when to introduce the Il-2 to the therapy. So Lets follow nature. Il-2 Is secreted after the CD4+ T cells are activated. THIS MEANS TIMING OF THE IL-2 IS CRUCIAL TO GENERATING A RESPONSE. How Long do we want to hold off before inoculation of the IL-2? We need the growth profiles of each of the CD4+ T cells.
Based on the data gather by Itoh and Colleagues we want to add the Il-2 at the Maximum propagation of the CD8+ T cells. I t has been reported that when the CD8+ T-cells are grown in the presence of Il-2 , they develop in to (CTL) Cytotoxic T Lymphocytes. That is just what we wanted.
This is where Itoh and Colleagues come in:
In 1988, a paper was published “Autologous 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 “ by Itoh and Colleagues. In their studies, they propagated (TILs) Tumor infiltrate lymphocytes cells from 12 Metastatic Melanoma patients. They preformed kinetic growth studies in IL-2 and even broke it down three Surface markers (CD3, CD4 and CD8).
The results are as follows:
The Total average maximum propagation was 43 days. (N=12)
The average maximum propagation for (lung, Axilla) was 40 days (n=3)
The average maximum propagation for (CD3) was 78 +/- 11 days (n=12)
The average maximum propagation for (CD4) was 33 +/- 10 days (n=12)
The average maximum propagation for CD4 (lung, Axilla) was 26 days (n=3)
The average maximum propagation for (CD8) was 49 +/- 17 days (n=12)
The average maximum propagation for CD8 (lung, Axilla) was 57 days (n=3)
Base on the above data, it would take about 49 days for my activated CD8+ T cells to reach maximum propagation. Then add the IL-2.
The Orchestration of an Inmmune Response Unrehearsed
Source: All Quotes are excerpts from Dr. Megan Levings’s Paper
So now if you put a clinical trial together and follow the timelines,
So now lets see My actual timeline.
They Always said Timing is Everything!!!!!
Take Care,
Jimmy B
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