Clonal expansion

Gradual diminution of 004 T-lymphocytes from the peripheral blood is the most consistent feature observed in HIV infection. Because the majority of 004 cells are T-helper lymphocytes, removal leads to deficiency of cellular immunity, which depends on T-helper cells to initiate cytotoxic T-ceU killing of vims-infected cells of cancer. The loss of immune surveillance leads to the appearance of viraHy induced tumors from unopposed clonal expansion of viraHy transformed cells. Furthermore, depletion of cellular immunity leads to exaggerated viral, fungal, and proto2oal infections. 

Humanized recombinant anti-IL-2 receptor antibodies (Basiliximab, Simulect , and Daclizumab Zenapax ). These antibodies bind with high affinity to the IL-2 receptor on T-lymphocytes and prevent activation and clonal expansion of anti-allograft T-lymphocytes by endogenous IL-2. They are used to prevent kidney allograft rejection. The main side effect is immunosuppression. 

These are supplied by the secretion of peptide molecules (termed cytokines or lymphokines) fiom a subset of the T-cell family (the helper T cells, TH cells). These peptide molecules (interleukins (IL) 2,4,5 and 6) stimulate the B cells to proliferate, undergo clonal expansion and mature into plasma cells which secrete antibody and also into the longer-hving, non-dividing memory cells. 

Once activated, T cells undergo clonal expansion (they multiply) under the influence of cytokines, specifically IL-2. These steps elicit an anti-donor T cell response that results in graft destruction. 

Basiliximab and daclizumab are considered monoclonal antibodies. Daclizumab is a humanized antibody that is approximately 10% murine and 90% human, whereas basiliximab is a chimeric antibody that is approximately 30% murine and 70% human.9,11 These agents bind with high affinity to the IL-2 receptor, where they act as CD25 receptor antagonists. These receptors are present on almost all activated T cells. Their role in induction therapy involves inhibiting IL-2-mediated activation of lymphocytes, which is an important step for the clonal expansion of T cells. 

Both AML and ALL are presumed to arise from clonal expansion of a single arrested cell. As these cells expand, they acquire one and often more chromosomal aberration, including translocations, inversions, deletions, point mutations, and... 

The T-lymphocyte receptor (TCR) is involved in detection of foreign antigens, presented together with the major histocompatibility complex (MHC). Subsequendy, it regulates the clonal expansion of T cells. 

The signaling complex formed around the TCR and the branching pathways that emanate from it resemble the mechanisms used by the growth factors. However, the destinations of these pathways are not all clear. The PLC-y pathway (DAG, IP3, and elevation of intracellular free Ca2+) leads to activation of the phosphatase calcineurin, which activates the transcription factor NF-AT (nuclear factor of activated T cells). This is essential for clonal expansion of T cells because of its pivotal role in the induction of IL-2 expression. NF-AT requires the assistance of the activator protein 1 (AP-1) complex in order to drive expression of IL-2. 

I immediate Soluble Clonal expansion B cells Cyto-philic antibody (IgE) generated binds to mast cells Antigen binds to cell bound antibody crosslinks receptors, causing release of mediators Anaphylactic response to bee sting immediate response in allergic asthma... 

II cytolytic Cell-associated Clonal expansion B cells IgM, IgG generated. Ig binds to cell bound antigen in the presence of complement and/or activated macrophages cell lysis occurs Rh factor incompatability, hemolytic anemeia in reaction to drugs... 

Thl Soluble Antigen presented by MHC II Clonal expansion CD4Thl Thl cells activated, release cytokines, activate macrophages, inflammation Tuberculin Rx, contact dermatitis, berylliosis... 

Th2 soluble Antigen presented by MHC II Clonal expansion CD4 Th2 Th2 cells activated Help for IgE production eosinophil and mast cell activation Chronic allergic rhinitis and asthma... 

CD8 Cell associated Antigen presented by MHC I clonal expansion of CD8 cells Activation of cytotoxic (CD-8) T cells Contact dermatitis (poison ivy) Chronic hypersensitivity pneumonitis... 

Figure 1.7. Lymphocyte activation. When naive lymphocytes first encounter the antigen that is recognised by their receptor, they are stimulated to differentiate and proliferate. This clonal expansion is aided by the production of cytokines. Two cell types develop from this process the effector cells (i.e. either antibody-secreting plasma cells or cytotoxic T cells) and memory cells. Both cell types possess virtually the same receptor that was expressed on the naive lymphocyte.

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