Therapeutic Uses of Cytokines and Their Receptors

The availability of purified cloned cytokines and soluble cytokine receptors offers the prospect of specific clinical therapies to modulate the immune response. A few cytokines—notably, interferons (see Clinical Focus)—and colony-stimulating factors, such as GM-CSF, have proven to be ther-apeutically useful. However, despite the promise of cytokines as powerful mediators of immune and other biological

(a) Suppression of TH-cell proliferation and T^-cell activation

Antibodies to IL-2R

(a) Suppression of TH-cell proliferation and T^-cell activation

Antibodies to IL-2R

Th cell

TC cell

Th cell

TC cell

IL-2 analogs

IL-2 analogs

Th cell

TC cell

Th cell

TC cell

(b) Destruction of activated Th cells

IL-2R

IL-2R

Th cell

Th cell

FIGURE 12-15

Experimental cytokine-related therapeutic agents offer the prospect of selectively modulating the immune response. (a) The anti-IL-2R monoclonal antibody binds to the cytokine recep tor (IL-2R) on the cell surface, thereby preventing interaction of the cytokine with its receptor. (b) Conjugation of a toxin with a cytokine results in destruction of cells expressing the cytokine receptor.

responses, not many have made their way into clinical practice. A number of factors are likely to raise difficulties in adapting cytokines for safe and effective routine medical use. One of these is the need to maintain effective dose levels over a clinically significant period of time. During an immune response, interacting cells produce sufficiently high concentrations of cytokines in the vicinity of target cells, but achieving such local concentrations when cytokines must be administered systemically for clinical treatment is difficult. In addition, cytokines often have a very short half-life, so that continuous administration may be required. For example, recombinant human IL-2 has a half-life of only 7-10 min when administered intravenously. Finally, cytokines are extremely potent biological response modifiers and they can cause unpredictable and undesirable side effects. The side effects from administration of recombinant IL-2, for instance, range from mild (e.g., fever, chills, diarrhea, and weight gain) to serious, such as anemia, thrombocytopenia, shock, respiratory distress, and coma. Despite these difficulties, the promise of cytokines for clinical medicine is great and efforts to develop safe and effective cytokine-related strategies continue, particularly in areas such as inflammation, cancer therapy, and modification of the immune response during organ transplantation, infectious disease, and allergy.

Some specific examples of various approaches being explored include cytokine receptor blockade and the use of cytokine analogs and cytokine-toxin conjugates. For instance, proliferation of activated TH cells and activation of TC cells can be blocked by anti-TAC, a monoclonal antibody that binds to the a subunit of the high-affinity IL-2 receptor (Figure 12-15a, left panel). Administration of anti-TAC has prolonged the survival of heart transplants in rats. Similar results have been obtained with IL-2 analogs that retain their ability to bind the IL-2 receptor but have lost their biological activity (Figure 12-15a, right panel). Such analogs have been produced by site-directed mutagenesis of cloned IL-2 genes. Finally, cytokines conjugated to various toxins (e.g., the p chain of diphtheria toxin) have been shown to diminish rejection of kidney and heart transplants in animals. Such conjugates containing IL-2 selectively bind to and kill activated Th cells (Figure 12-15b).

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