Section X - Drugs Used for Immunomodulation

- These cells are important in the normal immune response to infection and tumors but also mediate transplant rejection and autoimmunity (Janeway et al.
- lymphokines) that perform as effectors and regulators of the immune response..
- The impact of the immune system in human disease is enormous.
- Furthermore, one of the great therapeutic opportunities for the treatment of many disorders is organ transplantation.
- Krensky, et al.
- Brennan et al.
- mycophenolate mofetil (a purine metabolism inhibitor), each directed at a discrete site in T-cell activation (Suthanthiran et al.
- sirolimus are effective in preventing acute cellular rejection, they are not as effective in blocking T cells that already are activated, and they are not very effective against established, acute rejection or for the total prevention of chronic rejection (Monaco et al.
- Inhibitors of the Synthesis and Actions of Adrenocortical Hormones.
- Inhibitors of the Synthesis and Actions of Adrenocortical Hormones).
- Additionally, glucocorticoid-receptor complexes increase I B expression, thereby curtailing activation of NF B, which results in increased apoptosis of activated cells (Auphan et al.
- succinate ( SOLU-MEDROL , A-METHAPRED ) (pulses) are used to reverse acute transplant rejection and acute exacerbations of selected autoimmune disorders (Shinn et al.
- Laan et al.
- (From Pattison et al.
- Cyclosporine (cyclosporin A) is a cyclic polypeptide consisting of 11 amino acids, produced as a metabolite of the fungus species Beauveria nivea (Borel et al.
- a potent inhibitor of IL-2-stimulated T-cell proliferation and generation of cytotoxic T lymphocytes (CTL) (Khanna et al.
- The elimination of cyclosporine from the blood is generally biphasic, with a terminal half-life of 5 to 18 hours (Faulds et al.
- Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination) is linear within the therapeutic range, but the intersubject variability is so large that individual monitoring is required (Faulds et al.
- the time to peak blood concentrations is 1.5 to 2.0 hours (Faulds et al.
- Only 0.1% of cyclosporine is excreted unchanged in urine (Faulds et al.
- and psoriasis (Faulds et al.
- drugs must be monitored closely (Baraldo et al.
- Because of its mechanism of action, there is a theoretical basis for the use of cyclosporine in a variety of other T cell–mediated diseases (Faulds et al.
- The principal adverse reactions to cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, hyperlipidemia, and gum hyperplasia (Burke et al.
- Any drug that affects microsomal enzymes, especially the CYP3A system, may affect cyclosporine blood concentrations (Faulds et al.
- administration of the two drugs be separated by time.
- Tacrolimus ( PROGRAF , FK506) is a macrolide antibiotic produced by Streptomyces tsukubaensis (Goto et al.
- Tacrolimus is extensively metabolized in the liver by CYP3A, and at least some of the metabolites are active.
- levels of cyclosporine (Mayer et al.
- As with cyclosporine, nephrotoxicity is limiting (Mihatsch et al.
- cyclosporine (above) apply for tacrolimus as well (Venkataramanan et al.
- Yoshimura et al.
- RAPAMUNE ) is a macrocyclic lactone produced by Streptomyces hygroscopicus (Vezina, et al.
- Sirolimus inhibits T-lymphocyte activation and proliferation downstream of the IL-2 and other T- cell growth factor receptors (Figure 53–2) (Kuo et al.
- However, the sirolimus-FKBP-12 complex does not affect calcineurin activity, but binds to and inhibits the mammalian kinase, target of rapamycin (mTOR), which is a key enzyme in cell-cycle progression (Brown et al.
- below) (Groth et al.
- Seven major metabolites have been identified in whole blood (Salm et al.
- Sirolimus is indicated for prophylaxis of organ transplant rejection in combination therapy with a calcineurin inhibitor and glucocorticoids (Kahan et al.
- It is recommended that the maintenance dose be reduced by approximately one-third in patients with hepatic impairment (Watson et al.
- The use of sirolimus in renal transplant patients is associated with a dose-dependent increase in serum cholesterol and triglycerides that may require treatment (Murgia et al.
- Prophylaxis for Pneumocystis carinii pneumonia and cytomegalovirus is recommended (Groth et al.
- Since sirolimus is a substrate for cytochrome CYP3A4 and is transported by P-glycoprotein, close attention to interactions with other drugs that are metabolized or transported by these proteins is required (Yoshimura et al.
- 6-Thio-IMP, a fraudulent nucleotide, is converted to 6-thio-GMP and finally to 6-thio-GTP, which is incorporated into DNA and gene translation is inhibited (Chan et al.
- Azathioprine was first introduced as an immunosuppressive agent in 1961, helping to make allogeneic kidney transplantation possible (Murray et al.
- Xanthine oxidase, an enzyme of major importance in the catabolism of metabolites of azathioprine, is blocked by allopurinol (Venkat Raman, et al.
- Negligible amounts (<1%) of MPA are excreted in the urine (Bardsley-Elliot et al.
- safety and effectiveness in this population have not been established (Butani et al.
- Mycophenolate mofetil is indicated for prophylaxis of transplant rejection and is typically used in combination with glucocorticoids and a calcineurin inhibitor, but not with azathioprine (Kimball et al..
- Ahsan et al.
- Kreis et al., 2000).
- Bardsley-Elliot et al.
- Potential drug interactions between mycophenolate mofetil and several other drugs commonly used by transplant patients have been studied (Bardsley-Elliot et al.
- Antineoplastic Agents) are immunosuppressive due to their action on lymphocytes and other cells of the immune system.
- Cyclophosphamide and chlorambucil are used in treating childhood nephrotic syndrome (Neuhaus et al.
- Cyclophosphamide also is widely used for treatment of severe systemic lupus erythematosus (Valeri et al.
- (antilymphocyte globulin, ALS) into animals such as horses, rabbits, sheep, or goats and then purifying the serum immunoglobulin fraction (Mannick et al.
- Antithymocyte globulin ( THYMOGLOBULIN ) is a purified gamma globulin from the serum of rabbits immunized with human thymocytes (Regan et al.
- Antithymocyte globulin is indicated for induction immunosuppression and the treatment of acute renal transplant rejection in combination with other immunosuppressive agents (Mariat et al.
- is still used to reverse corticosteroid-resistant rejection episodes (Cosimi, et al.
- Muromonab-CD3 binds to CD3, a monomorphic component of the T-cell receptor complex involved in antigen recognition, cell signaling, and proliferation (Hooks et al.
- Woodle et al.
- Rostaing et al.
- Repeated use of muromonab-CD3 results in the immunization of the patient against the mouse determinants of the antibody, which can neutralize and prevent its immunosuppressive efficacy (Jaffers et al.
- In several studies, the production of the TNF- cytokine has been shown to be the major cause of the toxicity (Herbelin et al.
- to minimize the occurrence of anti-antibody responses and mutated to prevent binding to FcRs (Friend et al.
- In initial clinical trials, a humanized anti-CD3 monoclonal antibody that does not bind to FcRs reversed acute renal allograft rejection in the absence of the first-dose cytokine-release syndrome (Woodle et al.
- Anti–IL-2-receptor monoclonal antibodies are recommended for prophylaxis of acute organ rejection in adult patients as part of combination therapy (with glucocorticoids, a calcineurin inhibitor, with or without azathioprine or mycophenolate mofetil) (Kovarik et al.
- Kahan et al.
- Hirose et al., 2000).
- Renal transplant patients receiving 1 mg/kg of daclizumab intravenously every 14 days for 5 doses have saturating blockade of the IL-2 receptor for 120 days posttransplant (Vincenti et al.
- It is approved in the United States for treatment of the symptoms of rheumatoid arthritis in patients who have not responded to other treatments.
- In contrast, in these same model systems, sirolimus does not prevent tolerance and, in fact, in some cases promotes tolerance induction (Li et al.
- (Khoury et al.
- Preclinical studies have shown that inhibition of the costimulatory signal can induce tolerance (Larsen et al.
- Kirk et al.
- Other antagonists of T-cell costimulation, including anti-CD2, anti-ICAM-1 (CD54) and anti-LFA-1 monoclonal antibodies, have shown promise in preclinical models of tolerance (Salmela et al.
- (From Clayberger et al., 2001, with permission.).
- cyclophosphamide, and/or antibody treatment and then provide a new source of immune function by adoptive transfer (transfusion) of bone marrow or hematopoietic stem cells (Starzl et al.
- Fuchimoto et al.
- Spitzer et al.
- Hale et al., 2000).
- These findings gave rise to donor-specific transfusion protocols that gave improved outcomes (Opelz et al.
- Its only clinical indication is as an adjuvant treatment with fluorouracil after surgical resection in patients with Dukes' stage C colon cancer (Moertel et al.
- Figueredo et al.
- Lary et al.
- Nevertheless, it is indicated for the treatment of patients with erythema nodosum leprosum (ENL) (Sampaio et al.
- Its mechanism of action is unclear (Tseng et al.
- For example, thalidomide has been reported to decrease circulating TNF- in patients with ENL but to increase it in patients who are HIV-seropositive (Jacobson et al.
- The anti–TNF- effect has led to its evaluation as a treatment for severe, refractory rheumatoid arthritis (Keesal et al.
- primary and recurrent stage Ta and/or T1 papillary tumors following transurethral resection (Morales et al.
- Patard et al.
- Although interferons (alpha, beta, and gamma) initially were identified by their antiviral activity, these agents have important immunomodulatory activities as well (Johnson et al.
- In addition, it is supplied in combination with ribavirin ( REBETRON ) for treatment of chronic hepatitis C in patients with compensated liver function not treated previously with interferon alfa-2b or who have relapsed following interferon alfa-2b therapy (Lo Iacono et al., 2000).
- Further discussion of the use of these and other interferons in the treatment of viral diseases can be found in Chapter 50: Antimicrobial Agents: Antiviral Agents (Nonretroviral)..
- This recombinant form differs from native IL-2 in that it is not glycosylated, has no amino terminal alanine, and has a serine substituted for the cysteine at amino acid 125 (Doyle et al.
- and induction of interferon-gamma activity (Winkelhake et al.
- Although most work with vaccines has been aimed at infectious diseases, we are on the threshold of a new generation of vaccines aimed at specific cancers or autoimmune diseases (Lee et al.
- Simone et al.
- Jordan et al.
- Mycophenolate mofetil is replacing azathioprine as part of the standard immunosuppressive

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