Immune responses division

The consequence of ADA deficiency is accumulation of adenosine and 2 -deoxyadenosine, substances toxic to lymphocytes, important cells in the immune response. 2 -Deoxyadenosine is particularly toxic because its presence leads to accumulation of its nucleotide form, dATP, an essential substrate in DNA synthesis. Elevated levels of dATP actually block DNA replication and cell division by inhibiting synthesis of the other deoxynncleoside 5 -triphosphates (see Chapter 27). Accumulation of dATP also leads to selective depletion of cellular ATP, robbing cells of energy. Children with ADA SCID fail to develop normal immune responses and are susceptible to fatal infections, unless kept in protective isolation. 

Azathioprine [a zah THIO preen] has been the cornerstone of immunosuppressive therapy over the last several decades. It has a nitroimidazoloyl side chain attached to the sulfur of 6-mercap-topurine, which is removed by non-enzymatic reduction in the body by glutathione to yield 6-mercaptopurine (6-MP). The latter is then converted to the corresponding nucleotide, thioinosinic acid (TIMP), by the salvage pathway enzyme, hypoxanthine-gua-nine phosphoribosyl transferase. The immunosuppressant effects of azathioprine are due to this fraudulent nucleotide. (See pp. 380-381 for a discussion of 6-MP s mechanism of action, resistance, pharmacokinetics, and adverse effects.) Because of their rapid proliferation in the immune response, and their dependence on de novo synthesis of purines required for cell division, lymphocytes are predominantly affected by the cytotoxic effects of azathioprine. The drug has little effect on suppressing a secondary immune response. 

Interferons represent a class of proteins with various biological properties.338339 These include the ability to inhibit intracellular replication of viruses and certain parasites,340 the ability to inhibit replication of certain types of tumor cells in vitro, 41 and the ability to modulate immune responses in vitro and in vivo in a positive or negative manner.339 Of the interferons, interferon-y (IFN-y) is thought to be a more effective immunomodulary agent and a more effective inhibitor of division of certain tumor cells in vitro than other interferons.339 One mechanism of IFN-y-mediated growth inhibition is the stimulation of cellular oxidation of tryptophan by indoleamine 2,3-dioxygenase.342 343... 

The heterogeneity among Th cells is considerably more complex than a simple division into two discrete classes. Thl and Th2 cells must be regarded as being the most differentiated forms of CD4+ cells that develop from a common precursor or precursors as the immune response evolves. The immediate progenitor population is Th cells (designated ThO) that are... 

The division of T cells during the peak of the immune response is very rapid, often reaching three or four divisions per day. This would lead to more than a thousandfold increase in the number of selected T cells in a few days. 

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