Hand and Hand Tumor Rejection ..Melanoma ..Jim Breitfeller

This diagram goes with the "Tumor Rejection Piece"


Tumor Rejection!!!!!!

To cause the rejection of the tumors cells, The immune system must orchestrate a chain of events mediated by several types of Leukocytes including Dendtric cells (DC), Natuaral Killer cells (NK), CD4+ and CD8+ lymphocytes and others. This orchestration has many players in it including the T-Regs, sercreted cytokines, and Monoclonal antibodies (mAb’s) and complexes. It is a delicate balance between self and non-self.

At the Lymph Node drainage area, the lymphocytes (CD4+ and CD8+) with their T-cell receptors (TCRs) are able to scan the Dendtric cells (DC’s) for antigen-MHC molecules. (ag-MHC) major histocompatability complex (class I or II). Based on the two signal model, a second signal from CD28 molecule is needed to activate the T-cells (T-lymphocytes). If communcation breaksdown, and the TCR signal only happens, it can lead to tolerance by means of fuctional paralysis of the (APCs) Antigen presenting cells (Anergy) or by the induction of clonal deletion (apoptosis). Anergic cells can act as regulatory T cells by competing at the sites of antigen presentation and adsorbing out stimulatory cytokines such as IL-2. This can halt the activation of the T- lymphocytes and no immune response is initiated.

Once activated fully, the CD4+ T-cells can mobilize to where the event will take place and usually sends out a “danger signal” inflammation. The activated CD4+ T-cells can secrete many different cytokines including IL-4, IL-2 and activate the TH2 cells which are a subset of the CD4+ cells. The TH2 cells stimulate the B cells to mature into plasma cells that secrete antibodies. These antibodies that are produced are the cell-destructive kinds that have anti-tumor behavior. The CD4+ can also cross-prime CD8+ T-cells in the presence of IL-2 and are called (CTLs)Cytotoxic T Lymphocytes. Cross-priming is another name for cross-presentation. The role of the CD8+ T cells is to monitor all the cells of the body, ready to destroy any that express foreign antigen fragments in their class I molecules.

Some CD4+ T cells can develop into CTLs, but they can attack only those cell types (e.g. B cells, macrophages, dendritic cells) that express class II MHC molecules. Virtually every cell in the body expresses class I MHC molecules, so CD8+ CTLs are not limited in the targets they can attack. CTLs have cytoplasmic granules that contain the proteins perforin and granzymes. When the CTL binds to its target, the contents of the granules are discharged. A dozen or more perforin molecules insert themselves into the plasma membrane of target cells forming a pore that enables granzymes to enter the cell. Granzymes are serine proteases. The serine proteases are a family of enzymes that cut certain bonds in other proteins. It is similar to what is in your laundry detergent. They are known as detergent enzymes. They break the bond between the dirt and the fabric. By breaking up these proteins, they start destroying the intracellular workings of the tumor cells.

Next Piece is how the tumor protects itself from the Killer T-cells through a microenviroment and Tregs.


Just plugging away!!

Jimmy B