Antibodies clonal expansion

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. 

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. 

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... 

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.

In any battle, when the defence is outnumbered by the enemy, more troops are brought into the battle from the reserve. However, in the immune system, there are initially no reserve troops. When an antigen binds to its complementary antibody-receptor on B-cells, these are strongly stimulated to proliferate (clonal expansion). In addition, not only does the number of daughter cells increase but each quickly develops into what is known as an effector (or plasma) cell, in which the protein synthetic machinery increases through the development of the rough endoplasmic reticulum, so that there is a large increase in the number of antibodies synthesised and secreted. A simple description of the sequence of events is as follows ... 

Glucocorticoids inhibit acquired or cell-mediated immunity. Their effects are mediated via inhibition of genes that code for various cytokines. The cytokines inhibited by glucocorticoids include IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and IFN-y. IL-2 inhibition by corticosteroids is the most crucial effect in immunosuppression, which results in the inhibition of T-cell proliferation and activation of cytolytic T cells. Glucocorticoids also slightly affect humoral immunity by inhibiting B-cell clonal expansion and antibody synthesis, and these effects are mediated via their ability to inhibit B cells ability to express IL-2 and IL-2 receptors. 

Figure 19.2 The acquired immune response. In response to a specific antigen there is clonal expansion of B cells and subsequent production of antibodies (Ig) specific for that antigen. Antigen presenting cells process and present antigen to T cells. Again there is clonal expansion of cells specific for that antigen.

Remaining B-lymphocytes in the bone marrow have the potential to respond to an enormous number of foreign substances (antigens). Once exposed to antigens, the cells, which have the best fit antibody to the target, undergo clonal expansion to increase the cell numbers and affinity maturation to increase the specificity (fit) of the antibody molecules produced. 

Active B-cell undergoes clonal expansion, secretes antibodies to bind antigen I... 

Exposure to a specific antigen causes clonal expansion of all B cells capable of reacting with the multiple epitopes present on the antigen. Thus, the immune response to the entire antigen results in the production of antibodies by several clones of B cells. The resultant mixture of antibodies present in the serum is called a polyclonal antibody. In addition, because an animal is naturally exposed to a host of other antigens in its environment, its serum also contains antibodies produced by clones specific for each of these antigens. Therefore a polyclonal antibody preparation obtained from an animal is a mixture of many distinct antibody classes, only some of which are specific for the antigen used in experimental immunization. 

It is unlikely that IgE antibodies with extremely low affinity for allergen would have been detected in the experiments of Smurthwaite et al. [113]. Therefore, the B cells could have undergone affinity maturation, involving SHM and clonal expansion before or after migration into the tissue. But the expression of AID in the nasal mucosa makes this the more likely site. 

Clonal Expansion - A mechanism by which large-scale production of specific antibodies occurs. The B and T cells produced by the body have randomly generated antigen specificities. When a particular antigen enters the body, it induces proliferation only in B and T cells that happen to be specific for it. Thus, the antigen selects the cells that will mount an immune response against it and stimulates them to undergo clonal proliferation. 

Monoclonal and polyclonal antibodies directed at reactive T cells are important adjunct therapies and provide a unique opportunity to target specifically immune-reactive cells. Finally, newer small molecules and antibodies have expanded the arsenal of immunosuppressives. In particular, mTOR (mammalian target of rapamycin) inhibitors (sirolimus, everolimus) and anti-CD25 (interleukin [IL]-2 receptor) antibodies (basiliximab, daclizumab) target growth factor pathways, substantially limiting clonal expansion and potentially promoting tolerance. 

---