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It takes two (IL-2) to Tango!!!!!Immune responses involve multiple cell-cell interactions within lymphoid tissues, thetraf...
The model proposed by Dr. Dorothea Busse and colleages predicts that the IL-2secretion rate must exceed a threshold value ...
IL-2 is mainly captured by the Treg cell, whereas autocrine reuptake by the T helper cellspredominates when the cells are ...
Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectorsgenerated under these conditio...
Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectorsgenerated under these conditio...
Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectorsgenerated under these conditio...
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It takes two tango 2010

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Transcript of "It takes two tango 2010"

  1. 1. It takes two (IL-2) to Tango!!!!!Immune responses involve multiple cell-cell interactions within lymphoid tissues, thetrafficking of activated cells to sites of effector function, and the migration of sucheffector cells within peripheral tissues. To gain a more detailed appreciation of thedynamics of such cell behavior and the relationship between cell dynamics and function,I have put together a series of events that take place during the activation phase of theimmune response.We know based on research that once the CD4+ T cell is activated, within two hours theIL-2 expression and IL-2 receptor are unregulated. IL-2 is secreted 45 minutes into thisactivation phase.Experimental work has shown that IL-2 signaling in the first 10 hours is critical for theproliferation decision of T cells in culture. The spacial resolution of the Tregs and the Thelper cells during this phase plays a mojor part in the immune response.Secreted IL-2 is competed for by the Tregs and the activated CD4+ and CD8+ T-cells. Ifthe Tregs are in close proximity of the T effector cells, the Tregs will create an IL-2 sinkin the microenvironment. This will cause the proliferation and survival of the Tregs. ThisIL-2 sink is where all the IL-2 that is secreted by the T helper cells is adsorbed by the IL-2 receptors on the Tregs cell. Tregs don’t have the capability to produce IL-2. 1
  2. 2. The model proposed by Dr. Dorothea Busse and colleages predicts that the IL-2secretion rate must exceed a threshold value Theta (θ) to switch IL-2Rα expression to theactivated state and permit extensive autocrine IL-2 signaling.As you can see in the above diagram, you don’t need high concentration of IL-2, youneed spacial distance from one cell to the other. That can be achieved by Anti-CTLA-4Blockage. By blocking the CTLA-4 receptors, 2
  3. 3. IL-2 is mainly captured by the Treg cell, whereas autocrine reuptake by the T helper cellspredominates when the cells are further apart. So we want to introduce IL-2 before thetumor recruites the Tregs to the Tumor Microenviroment and or when the Tregpopulation is in the contration phase of the CD4+ T-cell cycle.Cellular signal response is potentially controlled by ratio between ligand (IL-2)number and surface receptor (IL-2R) number per cell. Sigmoid signal response is ageneral principle in different receptor trafficking networks.Suboptimal amounts of IL-2 during priming promoted apoptosis, little proliferation andcell cycling, yet the CD8+ effectors generated produced high levels of cytokines andproliferated autonomously. This is the reason why it takes a while for the Tumors tobegin to shrink because of little proliferation. 3
  4. 4. Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectorsgenerated under these conditions possessed optimal Effector functions.So how can we minimize the proliferation of the Tregs which are a subset of CD4+ T-cellsubset? 1. Anti-CTLA-4 Blockage 2. Local IL-21 Promotes the Therapeutic Activity of Effector T cells by Decreasing Regulatory T Cells Within the Tumor Microenvironment 3. Anti-PD-1 Blockage 4
  5. 5. Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectorsgenerated under these conditions possessed optimal Effector functions.So how can we minimize the proliferation of the Tregs which are a subset of CD4+ T-cellsubset? 1. Anti-CTLA-4 Blockage 2. Local IL-21 Promotes the Therapeutic Activity of Effector T cells by Decreasing Regulatory T Cells Within the Tumor Microenvironment 3. Anti-PD-1 Blockage 4
  6. 6. Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectorsgenerated under these conditions possessed optimal Effector functions.So how can we minimize the proliferation of the Tregs which are a subset of CD4+ T-cellsubset? 1. Anti-CTLA-4 Blockage 2. Local IL-21 Promotes the Therapeutic Activity of Effector T cells by Decreasing Regulatory T Cells Within the Tumor Microenvironment 3. Anti-PD-1 Blockage 4

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