**4.6 Apoptosis**

The final common pathway for cytolytic processes is the triggering of apoptosis in the target cell. After CTL activation, CTLs produce cytotoxic granules that contain perforin and granzymes. At the time of target cell identification and engagement, these granules fuse with the effector cell membrane and extrude their content into the immunological synapse. By a yet unknown mechanism, the granzymes are inserted into the target cell cytoplasm where granzyme B triggers apoptosis through several different mechanisms, including the

A link between self-MHC + allopeptide-primed T cells and the development of acute vascular rejection has been demonstrated to be mediated in part by accelerated alloantibody production. In addition, chronic allograft vasculopathy may be mediated by T cells primed

During T cell activation, membrane-bound inositol phospholipid is hydrolyzed into diacylglycerol (DAG) and IP3. This increases the concentration of cytoplasmic calcium. The elevation in calcium promotes the formation of calcium-calmodulin complexes that activate a number of kinases as well as protein phosphatase IIB or calcineurin. Calcineurin dephosphorylates cytoplasmic nuclear factor of activated T cells (NFAT), permitting its translocation to the nucleus, where it binds to the IL-2 promoter sequence and stimulates transcription of IL-2 mRNA. Numerous other intracellular events, including protein kinase C (PKC) activation by DAG and the activation of nuclear factor kappa B (NF-κB) also occur

Alloantigen-dependent and -independent factors contribute to the effector mechanisms. Initially, nonimmunologic "injury responses" (ischemia) induce a nonspecific inflammatory response. Because of this, antigen presentation to T cells is increased because of the upregulated expression of adhesion molecules, MHC class II, chemokines, and cytokines. It also promotes the shedding of intact, soluble MHC molecules that may activate the indirect allorecognition pathway. After activation, CD4 T cells initiate macrophage-mediated delayed type hypersensitivity (DTH) responses and provide help to B cells to initiate

Various T cells and T cell-derived cytokines such as IL-2 and IFN-γ are upregulated early after transplantation. Later, ß-chemokines, including regulated upon activation, normal T cell expressed and secreted (RANTES), IP-10, and MCP-1 are expressed, promoting intense macrophage infiltration of the allograft. IL-6, TNF-α, inducible nitric oxide synthase (iNOS) and growth factors also play a role in this process. Growth factors, including TGF-ß and endothelin, cause smooth muscle proliferation, intimal thickening, interstitial fibrosis, and,

Endothelial cells activated by T cell–derived cytokines and macrophages express MHC class II, adhesion molecules, and costimulatory molecules. Therefore, these cells can present antigen and recruit more T cells, amplifying the rejection process. CD8 T cells mediate cell-

The final common pathway for cytolytic processes is the triggering of apoptosis in the target cell. After CTL activation, CTLs produce cytotoxic granules that contain perforin and granzymes. At the time of target cell identification and engagement, these granules fuse with the effector cell membrane and extrude their content into the immunological synapse. By a yet unknown mechanism, the granzymes are inserted into the target cell cytoplasm where granzyme B triggers apoptosis through several different mechanisms, including the

by the indirect pathway[11].

at the molecular level[10].

antibody production.

**4.6 Apoptosis** 

in the case of the kidney, glomerulosclerosis.

mediated cytotoxicity reactions by inducing cell lysis or apoptosis.

*Effector stage* 

**4.5 Molecular mechanisms of T cell activation** 

direct cleavage of procaspase-3 and the indirect activation of procaspase-9. This has been shown to play the dominant role in apoptosis induction in allograft rejection.

Alternatively, CTLs can also use the Fas-dependent pathway to induce cytolysis and apoptosis. The Fas pathway is also important in limiting T cell proliferation in response to antigenic stimulation; this is known as fratricide between activated CTLs. Cell-mediated cytotoxicity has been shown to play an important role in acute, but not chronic, allograft rejection[12].
