New Immunosuppressive Drugs: Mechanistic Insights and Potential Therapeutic Advances

Overview

Journal Immunol Rev

Specialties Allergy & Immunology
General Surgery

Date 1993 Dec 1

PMID 8132204

Citations 10

Authors

A W Thomson

T E Starzl

Affiliations

Soon will be listed here.

Abstract

Together with CsA, the new macrolide immunosuppressants FK506 and rapamycin have proved to be valuable tools in providing new information about key molecular events that underlie lymphocyte activation and degranulation. Studies of their mechanisms of action have pinpointed the phosphatase calcineurin and protein kinases as important signaling mediators in T-cell activation. Other new immunosuppressive drugs, including leflunomide, mycophenolate mofetil, brequinar sodium and deoxyspergualin exhibit diverse inhibitory effects on cells of the immune system and offer considerable promise as adjunctive therapeutic immunosuppressants. FK506 appears to be both a valuable therapeutic alternative to liver or kidney retransplantation and an alternative primary immunosuppressant to CsA in hepatic (especially) and renal transplantation. There is now good evidence that immunosuppressive drugs, both old and new, permit the establishment of donor-derived, multi-lineage cell chimerism following organ transplantation.

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References

Schreiber S . Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science. 1991; 251(4991):283-7. DOI: 10.1126/science.1702904. View

Amemiya H, Suzuki S, Ota K, Takahashi K, Sonoda T, Ishibashi M . A novel rescue drug, 15-deoxyspergualin. First clinical trials for recurrent graft rejection in renal recipients. Transplantation. 1990; 49(2):337-43. View

Kuo C, Chung J, Fiorentino D, Flanagan W, Blenis J, Crabtree G . Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature. 1992; 358(6381):70-3. DOI: 10.1038/358070a0. View

Starzl T, Demetris A, Trucco M, Murase N, Ricordi C, Ildstad S . Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology. 1993; 17(6):1127-52. PMC: 2964270. View

Clipstone N, Crabtree G . Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature. 1992; 357(6380):695-7. DOI: 10.1038/357695a0. View

Mueller D, Jenkins M, Schwartz R . Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989; 7:445-80. DOI: 10.1146/annurev.iy.07.040189.002305. View

OKeefe S, Tamura J, Kincaid R, Tocci M, ONeill E . FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin. Nature. 1992; 357(6380):692-4. DOI: 10.1038/357692a0. View

Peters D, Fitton A, Plosker G, Faulds D . Tacrolimus. A review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs. 1993; 46(4):746-94. DOI: 10.2165/00003495-199346040-00009. View

Flanagan W, Crabtree G . Rapamycin inhibits p34cdc2 expression and arrests T lymphocyte proliferation at the G1/S transition. Ann N Y Acad Sci. 1993; 696:31-7. DOI: 10.1111/j.1749-6632.1993.tb17139.x. View

10.

Murase N, Demetris A, Matsuzaki T, Yagihashi A, Todo S, Fung J . Long survival in rats after multivisceral versus isolated small-bowel allotransplantation under FK 506. Surgery. 1991; 110(1):87-98. PMC: 2975982. View

11.

Amemiya H, Dohi K, Otsubo O, Endo T, Nagano S, Ishibashi M . Markedly enhanced therapeutic effect of deoxyspergualin on acute rejection when combined with methylprednisolone in kidney recipients. Transplant Proc. 1991; 23(1 Pt 2):1087-9. View

12.

Chong A, Finnegan A, Jiang X, Gebel H, Sankary H, Foster P . Leflunomide, a novel immunosuppressive agent. The mechanism of inhibition of T cell proliferation. Transplantation. 1993; 55(6):1361-6. DOI: 10.1097/00007890-199306000-00028. View

13.

Woo J, Valdivia L, Pan F, Celli S, Fung J, Thomson A . Cytidine potentiates the inhibitory effect of brequinar sodium on xeno-MLR, antibody production, and concordant hamster to rat cardiac xenograft survival. Ann N Y Acad Sci. 1993; 696:227-34. DOI: 10.1111/j.1749-6632.1993.tb17155.x. View

14.

Price D, Grove J, Calvo V, Avruch J, Bierer B . Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science. 1992; 257(5072):973-7. DOI: 10.1126/science.1380182. View

15.

Tamura K, Woo J, Bakri M, Thomson A . Brequinar sodium inhibits interleukin-6-induced differentiation of a human B-cell line into IgM-secreting plasma cells. Immunology. 1993; 79(4):587-93. PMC: 1421916. View

16.

Starzl T, Demetris A, Murase N, Thomson A, Trucco M, Ricordi C . Donor cell chimerism permitted by immunosuppressive drugs: a new view of organ transplantation. Immunol Today. 1993; 14(6):326-32. PMC: 2979321. DOI: 10.1016/0167-5699(93)90054-o. View

17.

Fuchs E, Matzinger P . B cells turn off virgin but not memory T cells. Science. 1992; 258(5085):1156-9. DOI: 10.1126/science.1439825. View

18.

Murase N, Kim D, Todo S, Cramer D, Fung J, Starzl T . Induction of liver, heart, and multivisceral graft acceptance with a short course of FK 506. Transplant Proc. 1990; 22(1):74-5. PMC: 2903852. View

19.

Gaylord H, Brennan P . Leprosy and the leprosy bacillus: recent developments in characterization of antigens and immunology of the disease. Annu Rev Microbiol. 1987; 41:645-75. DOI: 10.1146/annurev.mi.41.100187.003241. View

20.

Xu Q, Leiva M, Fischkoff S, Handschumacher R, Lyttle C . Leukocyte chemotactic activity of cyclophilin. J Biol Chem. 1992; 267(17):11968-71. View