Blocking co-stimulatory pathways, as noted above in connection with the prevention of transplantation rejection (see Section 16-6), has also been applied to autoimmune diseases. For example, CTLA-4–Ig (abatacept) blocks the interaction of the B7 expressed by antigen-presenting cells with the CD28 expressed by T cells. This drug is approved for the treatment of rheumatoid arthritis, and also seems to be beneficial in treating psoriasis. When CTLA-4–Ig was given to patients with psoriasis, there was an improvement in the psoriatic rash and histological evidence of loss of activation of keratinocytes, T cells, and dendritic cells within the damaged skin.
Another co-stimulatory pathway that has been targeted in psoriasis is the interaction between the adhesion molecule CD2 on T cells and CD58 (LFA-3) on antigen-presenting cells. A recombinant CD58–IgG1 fusion protein, called alefacept (Amevive), inhibits the interaction between CD2 and CD58, and is now a routine and effective treatment for psoriasis. Although memory T cells are targeted by this therapy, responses to vaccination such as antitetanus remain intact.
16-11 Some commonly used drugs have immunomodulatory properties.
Certain existing medications, such as the statins and angiotensin-converting enzyme (ACE) inhibitors widely used in the prevention and treatment of cardiovascular disease, can also modulate the immune response in experimental animals. Statins are very widely prescribed drugs that block the enzyme 3-hydroxy-3-methylglutaryl-co-enzyme A (HMG-CoA) reductase, thereby reducing cholesterol levels. They also reduce the increased level of expression of MHC class II molecules in some autoimmune diseases. These effects may be due to an alteration in the cholesterol content of membranes, thereby influencing lymphocyte signaling. In animal models, these drugs also seem to cause T cells to switch from a more pathogenic TH1 response to a more protective TH2 response, although whether this occurs in human patients is not clear.
The hormone vitamin D3, essential for bone and mineral homeostasis, also exerts immunomodulatory effects. It decreases IL-12 production by dendritic cells and leads to a decrease in IL-2 and IFN-γ production by CD4 T cells, and
Fig. 16.10 Treatment with an anti-α4 integrin humanized monoclonal antibody reduces relapses in multiple sclerosis. Left panel: interaction between α4:β1 integrin (VLA-4) on lymphocytes and macrophages and VCAM-1 expressed on endothelial cells permits the adhesion of these cells to brain endothelium. This facilitates the migration of these cells into the plaques of inflammation in multiple sclerosis. Center panel: the monoclonal antibody natalizumab (blue) binds to the α4 chain of the integrin and blocks adhesive interactions between lymphocytes and monocytes and VCAM-1 on endothelial cells, thus preventing the cells from entering the tissue and exacerbating the inflammation. The future of this treatment is unclear because of the development of a rare infection as a side-effect (see the text). Right panel: the number of new lesions detected on magnetic resonance imaging (MRI) of the brain is greatly reduced in patients treated with natalizumab compared with a placebo. Data from Miller, D.H., et al.:
N. Engl. J. Med. 2003, 348:15–23.