Déjà vu blame it on the tregs


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Déjà vu blame it on the tregs

  1. 1. Déjà vu.. Blame it on the Tregs!!!!!!As I reevaluate my theory, I have come full circle in my research and came across theresearch paper entitled:The Role of Regulatory T Cells in CancerTai-You Ha*Department of Immunology, Chonbuk National University Medical School, Chonju,Chonbuk, Korea<A HREF="https://www.box.net/shared/ygz27ma9vn">The Role of Regulatory T Cellsin Cancer</A> <BR>I postulate that the T regulatory cells may be the major stumbling block in the wholeimmunotherapy. Recent studies have shown that CD4+CD25high FoxP3+ Treg cells areoverrepresented in human metastatic lymph nodes with a 2-fold increased frequencycompared with both tumor-free lymph nodes and that advanced melanoma is associatedwith increased numbers of circulating Treg cells and Dendritic Cells (DCs) and suggestedthat melanoma induces immunosuppressive DCs and Treg cells in the systemiccirculation of the patients . Vence et al also showed the presence of tumor antigen-specific CD4+ Treg cells in the blood of patients with metastatic melanoma.This means the host (you) may already have the correct antigen, but the tumor andmicroenvironment may be suppressing the immune response by secreting suppressivecytokines like TGF- beta , IL-10, and IL -6 and or proliferating the suppressive Tregs. Nicholaou et al most recently showed in patients with melanoma that although strongantibody responses were mounted, the generation of delayed-type hypersensitivity 1
  2. 2. response was significantly impaired and patients with advanced melanoma had asignificantly higher proportion of circulating CD4+ CD25+FoxP3+ Treg cellscompared with those with minimal residual disease. So we now can blame the toleranceof our immune system to cancer on the T Regulatory Cells (Tregs).It has been reported that the large number of different cell types that are claiming to bedirectly targeted by FoxP3+ Treg cells are CD4+, CD8+ T cell, dendritic cells, Bcells, marophages, osteoblasts, mast cells, NK cells, and NKT cells.No wonder our immune system can’t raise an attack on the Melanoma. The tumor is likea castle in the middle ages. The castle (tumor) is surrounded by a moat the (suppressivecytokines) and the walls and towers are the Tregs. If you take out walls and tower, thecastle becomes vulnerable. 2
  3. 3. These Tregs when activated, upregulate the CTLA-4, CD25 (IL-2), and other receptors.So if you control the function of the Tregs, you may be able to break the tolerance of theimmune system. This can be done by blocking receptors on the Treg cells 3
  4. 4. It was also noted as the tumor burden increased, so did the Tregs in the peripheral whichmakes it harder to eradicate tumors in the advanced stage of Melanoma.Wieczorek et al found that Treg cell numbers are significantly increased in the peripheralblood of patients with IL-2-treated melanoma. IL-2 stimulates CXCR4 expressed on theTregs enables the Tregs to migrate CxCL12 in the tumor microenvironment increasingthe Treg accumulation. So we need to deplete, block and limit the expansion of the Tregs. We also want to limitthe concentration of Interluekin-2 at the early stage of the CD4+ T-cell expansion. Thiscan be done in a number of ways, but why not use an antibodies that can indirectlyaccomplish both tasks at once. By using anti-CTLA-4 blockage we keep the activationgoing, causing a free for all for the cytokine IL-2 that is secreted.CD4+ T cells regulate immune responses by producing various cytokines upon antigenstimulation. Naive CD4+ T cells have limited cytokine responses and secrete only IL-2before they differentiate into various effector cell types CD4+ T cells regulate immuneresponses by producing various cytokines upon antigen stimulation. Each cell type iscompeting for a limited amount of IL-2 secreted by a small subset of the T helper cells.Naive T cells stimulated with antigen in the presence of IL-4 differentiate into Th2 cellssecreting IL-4, IL-5, IL-10, and IL-13, whereas IL-12 induces the differentiation of naivecells into Th1 cells secreting IL-2, IFN-γ, and lymphotoxin. 4
  5. 5. FROM:Autoimmunity: IL-21: a new player in Th17-cell differentiationElissa K Deenick and Stuart G TangyeWWW.Nature.comRibas and Restifo et al found that if you use Anti-CTLA-4 blockade the native T-cell ispushed towards the Th17 differentiation. This causes less interleukin-2 to be produced bythe CD4+ T-cells causing a shortage of IL-2 in the microenvironment for the expandingT-cells thus limiting the differentiation to Tregs. It is well known that in the presence ofTGF-beta and IL-2, the Native T-cell differentiates into T Regulatory Cells.Also the activation and differentiation of Naïve CD8+ T cells require IL-2 provided byactivated CD4+ T cells at the initial priming stage within 0–2.5 hours after stimulation.Thers is critical IL-2 signal from CD4+ cells is mediated through the IL-2R (receptor) of NaïveCD8+ cells. This activation of IL-2 signaling advances the restriction point of the cell 5
  6. 6. cycle, and thereby expedites the entry of antigen-stimulated Naïve CD8+ T-cell into the Sphase of the cell cycle.The cell cycle has four stages: 1. G1 phase when the cell increases in size and gets ready to replicate its DNA. 2. S phase when the cell synthesizes or copies its chromosomes 3. G2 phase in which the cell prepares to divide 4. M phase when mitosis occurs.If no IL-2 is available to Naïve CD8+ T-cells, they never get a chance to expand anddifferentiate into Ctotoxic T Lymphocytes (CTLs) Killer T-cells.Besides promoting cell proliferation, IL-2 stimulation increases the amount of IFNγ andgranzyme B produced by CD8+ T cells.Activation and Differentiation of (CTLs) Cytotoxic T LymphocytesNaïve CD8+ T-cells are referred to as CTL-precursors (CTL-Ps), which are incapable ofperforming any function other then recognizing the class I MHC-antigen complex on theTumor cells through the (TCR) T Cell Receptor. For activation, the CTL-P needs at leastthree signals: 1. Antigen specific signal transmitted by the MHC I peptide/TCR complex for the recognition of the Antigen 2. The Costimulatory signals transmitted by the CD28 receptor and the B7 molecule of the Antigen Presenting Cells (APCs) 3. Cytokine induced signal, IL-2 interaction with the IL-2r (receptor) on the CTL-P leading to activation and differentiation of the CTL-P into effector CTLThe Cytokine IL-2 came from the(CD4+) TH1 cells which means the CTL-P is IL-2limited and can only be activated by the secreted IL-2 if there is any to be had or byintroducing IL-2 through IL-2 therapy. Now you know the reasoning behind using theIL-2 therapy as the second part of the combinatorial Therapy. If there is not enough IL-2in the host environment, you will only get partial expansion of the CTLs. It may not beenough to eradicate large bulky tumors. 6
  7. 7. The Interluekin-2 plays another role in this Melanoma Maze. In a study by Janas et al, Il-2 increases the expressions of the perforin and granzyme A, B and C genes in the CD8+T-cells. This increase expression causes the CD8+ T-cells to mature into Cytoxic TLymphocytes (CTLs). The exogenous IL-2 is required for the granzyme proteins. CTLshave cytoplasmic granules that contain the proteins perforin and granzymes. A dozen ormore perforin molecules insert themselves into the plasma membrane of target cellsforming a pore that enables granzymes to enter the cell. Once in the tumor cell, theseenzymes are able to breakup (lyse) the cell and destroy it. This is the beginning of the endfor the cancer cells. The tumors begin to shrink and the rest is history.Research suggests that the primary mode of the destruction of the tumors by CTL is byinitiating death through the Fas-FasL pathway. Studies have shown that CTLs storeCytotoxic proteins in the form of granules in their cytoplasm. These proteins belong totwo categories: 1. Perforins: involved in pore formation 2. Granzymes: responsible for hydrolysis of the cellular products.Granzymes breaks down the tumors cells just like your detergent enzymes in yourlaundry detergent.Immediately following a CTL contact with the tumor cell, the Golgi sacks load withgranules and granzymes which create pores to allow the granzymes to enter and destroythe tumors cells.So now you know why Anti-CTLA-4 blockage and HD Interluekin-2 go hand and hand.Timing of the addition of IL-2 can make or break the immune response. And withoutsuppressing the Tregs, your chances to mount an immune response may be slim at best.Your Immune System is a well Orchestrated system of events; we just need theKnowledge on how to harvest its potential on eradicating cancer. 7
  8. 8. The beginning of knowledge is the discovery of something we do not understand.~Frank Hebert~A critically acclaimed and commercially successful American science fiction author 8
  9. 9. The beginning of knowledge is the discovery of something we do not understand.~Frank Hebert~A critically acclaimed and commercially successful American science fiction author 8
  10. 10. The beginning of knowledge is the discovery of something we do not understand.~Frank Hebert~A critically acclaimed and commercially successful American science fiction author 8