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Immunoregulatory drugs: mechanistic basis for use in organ transplantation
1Rogosin Institute, Department of Transplantation Medicine and Extracorporeal Therapy, New York, USA.
Abstract:
Multiple immunoregulatory drugs, capable of constraining cell activation, differentiation, and/or proliferation, and each with distinct side effects, are currently used in the clinic to facilitate organ engraftment. Cyclosporine, azathioprine, corticosteroids, FK506 (tacrolimus), and RS61443 (mycophenolate mofetil) have already been approved by the United States Food and Drug Administration. Rapamycin (sirolimus), mizoribine, and 15-deoxyspergualin are being explored for their clinical efficacy. Based on their subcellular site of action, the immunosuppressants can be considered as: inhibitors of transcription (cyclosporine, tacrolimus), inhibitors of nucleotide synthesis (azathioprine, mycophenolate mofetil, mizoribine), inhibitors of growth factor signal transduction (sirolimus), and inhibitors of differentiation (15-deoxyspergualin). Clearly, the transplant clinician now has a greater choice in the selection and application of immunosuppressants in the clinic for the fine regulation of anti-allograft immunity. The existing hypothesis regarding the mechanisms of action of immunosuppressants is that they all function to prevent allograft rejection by preventing/inhibiting cell activation, cytokine production, differentiation, and/or proliferation. A complementary supposition is that some of the immunosuppressants might regulate the anti-allograft repertory by stimulating the expression of immunosuppressive molecules and/or cells.
Insights
Organ engraftment relies on immunoregulatory drugs that inhibit immune responses. These drugs target various cellular processes, offering clinicians diverse options for managing anti-allograft immunity and preventing transplant rejection.
Area of Science:
- Immunology
- Pharmacology
- Transplantation
Background:
- Organ engraftment requires immunoregulatory drugs to manage the recipient's immune response.
- Several immunosuppressants are approved, with others under clinical investigation for efficacy.
Purpose of the Study:
- To categorize existing and emerging immunosuppressants based on their subcellular mechanisms of action.
- To highlight the expanding therapeutic options for transplant clinicians in regulating anti-allograft immunity.
Main Methods:
- Classification of immunosuppressants by their site of action (e.g., transcription inhibition, nucleotide synthesis inhibition).
- Review of approved and investigational drugs like cyclosporine, azathioprine, mycophenolate mofetil, sirolimus, and 15-deoxyspergualin.
Main Results:
- Immunosuppressants function by inhibiting cell activation, cytokine production, differentiation, or proliferation.
- Drugs are categorized into inhibitors of transcription, nucleotide synthesis, signal transduction, and differentiation.
Conclusions:
- Clinicians have a broader selection of immunosuppressants for precise regulation of anti-allograft immunity.
- The mechanisms of action, while diverse, collectively aim to prevent allograft rejection, with potential roles in stimulating immunosuppressive factors.