**2.1. Cyclosporine A (CsA)**

CsA is a cyclic polypeptide immunosuppressant consisting of 11 amino acids. It is produced as a metabolite of the fungus species *Tolypocladium inflatum* Gams. CsA generally is recognized as the agent that ushered in the modern era of organ transplantation, increasing the rates of early engraftment, extending kidney graft survival, and making cardiac and liver transplan‐ tation possible. Clinical indications for CsA are kidney, liver, heart, and other organ trans‐ plantation; rheumatoid arthritis; and psoriasis. The dose of CsA varies, depending on the organ transplanted and the other drugs used in the specific treatment protocols. Dosage is guided by signs of rejection (too low a dose), renal or other toxicity (too high a dose), and close monitoring of blood levels [1].

#### *2.1.1. Mechanism of action*

CsA suppresses some humoral immunity, but is more effective against T-cell-dependent immune mechanisms such as those underlying transplant rejection and some forms of autoimmunity. Its actions appear to be dependent upon binding to intracellular sites of action. Because of its high lipophilicity, CsA enters cells easily to gain access to the site of action [1]. The intracellular protein most closely linked to the immunosuppressive activity of CsA is cyclophilin. CsA forms a complex with cyclophilin, a cytoplasmic receptor protein present in target cells. This complex binds to calcineurin to block its phosphatase activity (Table 1). Calcineurin-catalyzed dephosphorylation is required for movement of a component of the nuclear factor of activated T lymphocytes (NFAT) into the nucleus. Calcineurin phosphatase activity is inhibited after physical interaction with the cyclosporine/cyclophilin complex. This prevents Ca2+-stimulated dephosphorylation of the cytosolic component of NFAT such that NFAT does not enter the nucleus, gene transcription is not activated, and the T lymphocyte fails to respond to specific antigenic stimulation. By binding to cyclophilin, the antigenic response of helper T lymphocytes is inhibited; the production of interleukin-2 and interferongamma is suppressed [2-3]. In addition, production of the receptor site for interleukin-2 on T lymphocytes is inhibited by CsA and also increases expression of transforming growth factorβ (TGF-β), a potent inhibitor of IL-2–stimulated Tcell proliferation and generation of cytotoxic T lymphocytes (CTL) [4-8].

#### *2.1.2. Side effects*

The principal side effects to CsA therapy are hypertension, nephrotoxicity, tremor, hirsutism, hyperlipidemia, nausea and vomiting, gingival hyperplasia, and hepatotoxicity [1,9]. Hyper‐ tension is a common adverse effect of CsA, with the incidence decreasing over time. Generally, mild to moderate hypertension may occur in approximately 50% of renal transplant patients and most cardiac transplant patients. In liver transplant patients (n=75), 27% experienced hypertension. Incidence: 13% to 53% [9]. Discontinuation of CsA therapy may be required for persistent blood pressure elevation despite adjustments in therapy. Antihypertensive agents such as calcium-channel blockers may be used, with isradipine and nifedipine most appro‐ priate since they do not interfere with CsA metabolism. Other calcium-channel blockers (eg, diltiazem and verapamil) may increase cyclosporine levels. Patients with preexisting hyper‐ tension controlled by beta-blockers may continue to receive the same therapy. Angiotensin converting enzyme inhibitors and diuretics are not recommended [10]. Probable mechanisms for cyclosporine induced hypertension involve increased prostaglandin synthesis, decreased free water excretion, and decreased sodium and potassium excretion [11]. CsA is nephrotoxic, the mechanism by which CsA causes nephrotoxicity is attributed to changes in vasomotor tone induced by activation of the sympathetic nervous system [12]. Tremor was reported to appear within a few days of initiating CsA therapy and was considered dose dependent. Incidence: 12% to 55% [9].

and concluding with brief information about monitoring of individual immunosuppressive

CsA is a cyclic polypeptide immunosuppressant consisting of 11 amino acids. It is produced as a metabolite of the fungus species *Tolypocladium inflatum* Gams. CsA generally is recognized as the agent that ushered in the modern era of organ transplantation, increasing the rates of early engraftment, extending kidney graft survival, and making cardiac and liver transplan‐ tation possible. Clinical indications for CsA are kidney, liver, heart, and other organ trans‐ plantation; rheumatoid arthritis; and psoriasis. The dose of CsA varies, depending on the organ transplanted and the other drugs used in the specific treatment protocols. Dosage is guided by signs of rejection (too low a dose), renal or other toxicity (too high a dose), and close

CsA suppresses some humoral immunity, but is more effective against T-cell-dependent immune mechanisms such as those underlying transplant rejection and some forms of autoimmunity. Its actions appear to be dependent upon binding to intracellular sites of action. Because of its high lipophilicity, CsA enters cells easily to gain access to the site of action [1]. The intracellular protein most closely linked to the immunosuppressive activity of CsA is cyclophilin. CsA forms a complex with cyclophilin, a cytoplasmic receptor protein present in target cells. This complex binds to calcineurin to block its phosphatase activity (Table 1). Calcineurin-catalyzed dephosphorylation is required for movement of a component of the nuclear factor of activated T lymphocytes (NFAT) into the nucleus. Calcineurin phosphatase activity is inhibited after physical interaction with the cyclosporine/cyclophilin complex. This prevents Ca2+-stimulated dephosphorylation of the cytosolic component of NFAT such that NFAT does not enter the nucleus, gene transcription is not activated, and the T lymphocyte fails to respond to specific antigenic stimulation. By binding to cyclophilin, the antigenic response of helper T lymphocytes is inhibited; the production of interleukin-2 and interferongamma is suppressed [2-3]. In addition, production of the receptor site for interleukin-2 on T lymphocytes is inhibited by CsA and also increases expression of transforming growth factorβ (TGF-β), a potent inhibitor of IL-2–stimulated Tcell proliferation and generation of cytotoxic

The principal side effects to CsA therapy are hypertension, nephrotoxicity, tremor, hirsutism, hyperlipidemia, nausea and vomiting, gingival hyperplasia, and hepatotoxicity [1,9]. Hyper‐ tension is a common adverse effect of CsA, with the incidence decreasing over time. Generally,

agents as well as a brief description of future trends in immunosuppression therapy.

**2. Mechanism of action and side effects**

310 Current Issues and Future Direction in Kidney Transplantation

**2.1. Cyclosporine A (CsA)**

monitoring of blood levels [1].

*2.1.1. Mechanism of action*

T lymphocytes (CTL) [4-8].

*2.1.2. Side effects*


**Table 1.** Sites of action of immunosuppressive agents on T-cell activation [1]

Administration of CsA adversely affects plasma lipoprotein and cholesterol levels causing hyperlipidemia [9]. In a study CsA increased total cholesterol by 21%, low-density lipoproteins by 31%, and apolipoproteins by 12% over 27 days [13]. Gingival hyperplasia was reported in 4% to 16% of patients treated with CsA [9]. Histologically, CsA-induced gingival overgrowth is characterized by cellular hyperplasia along with myxomatous changes and accumulation of collagen [14]. Reduction of the dose of CsA may result in complete resolution of gingival hyperplasia [15,16].
