Immunosuppression with cyclosporin A: a review.

The cyclic peptide cyclosporin A (CS-A) is a fungal metabolite which has only a narrow spectrum of antibiotic activity but profound effects on immune responses, including inhibition of cell-mediated cytolysis, graft-versus-host and delayed-type hypersensitivity reactions. It has a high affinity for membrane lipids and probably interferes with an early event in RNA and DNA synthesis. The compound has a remarkably specific affinity for lymphocytes which in most species of animal appears to be more marked for T-cells but in man may be equal in T- and B-cells. Other cell types including myeloid cells are spared its effects. Most evidence suggests that CS-A interferes with an early event during transformation from the resting to the blast cell state, probably the actual acquisition of responsiveness to growth factors; it does not affect already converted lymphoblasts; it lacks anti-mitotic activity and cytotoxic effects on lymphocytes, granulocytes or monocytes; it allows recovery of proliferative capacity once removed from the system; and it has no acute anti-inflammatory activity. Whether CS-A specifically inhibits T-helper cells relative to T-suppressor cell populations has not yet been determined but this seems likely, and most evidence suggests that clones of cells are attenuated for varying lengths of time rather than deleted. The immunosuppressive potency of CS-A has been amply demonstrated in a wide range of species when used to protect many different allografts and even xenografts. Results in clinical practice are promising but marred at present by a worrying incidence of lymphomas and infections when given in combination with other conventional immunosuppressants. CS-A should be regarded as the first in a new generation of suppressive agents not with euphoria, but with cautious optimism.