Selective immunosuppressants

Selective immunosuppressants represent a specialized category of pharmaceutical agents designed to modulate or suppress specific components of the immune system. Unlike broad-spectrum immunosuppressants (e.g., corticosteroids, cytotoxic agents), these drugs selectively target distinct molecular pathways, cellular receptors, or immune cell subtypes involved in pathologic immune activation. Their increased specificity allows for improved efficacy with a reduced profile of generalized immune suppression, making them vital in autoimmune diseases, organ transplantation, and inflammatory disorders.

This drug class encompasses agents that inhibit T-cell activation, block co-stimulatory signals, antagonize interleukin receptors, or suppress key transcription factors in immune signaling cascades. Selective immunosuppressants are widely used in diseases such as rheumatoid arthritis (RA), psoriasis, multiple sclerosis (MS), Crohn’s disease, and in preventing graft rejection after organ transplantation.

---

1. Definition and Pharmacological Basis

Selective immunosuppressants are drugs that target specific immune pathways involved in the activation and proliferation of immune cells. These agents differ from non-selective immunosuppressants in that they:

• Do not indiscriminately suppress all immune responses

• Are less toxic to non-immune tissues

• Are designed to spare protective immunity (e.g., response to vaccines and infections)

• Offer precision therapy for chronic autoimmune and inflammatory diseases

They work through several mechanisms:

• Blocking T-cell receptor signaling

• Inhibiting cytokine pathways (e.g., IL-2, IL-6, IL-12/23)

• Modulating immune checkpoints (e.g., CTLA-4, CD80/86)

• Preventing clonal expansion of lymphocytes

---

2. Major Classes and Representative Agents

A. Calcineurin Inhibitors (CNIs)

These agents block the phosphatase calcineurin, preventing nuclear factor of activated T-cells (NFAT) from initiating IL-2 transcription—thereby inhibiting T-cell activation.

1. Cyclosporine

   • Indications: Organ transplantation, psoriasis, RA, nephrotic syndrome

   • Formulations: Capsules, oral solution, IV injection, eye drops (Restasis)

   • Metabolism: CYP3A4

   • Adverse Effects: Nephrotoxicity, hypertension, hirsutism

2. Tacrolimus

   • Indications: Organ transplantation (especially liver, kidney), atopic dermatitis (topical), uveitis

   • Formulations: Oral, IV, topical (Protopic)

   • Potency: 10–100x more potent than cyclosporine

   • Adverse Effects: Hyperglycemia, neurotoxicity, nephrotoxicity

B. mTOR Inhibitors (Mammalian Target of Rapamycin)

These agents inhibit mTOR, which is required for cell cycle progression in activated T-lymphocytes.

1. Sirolimus (Rapamycin)

   • Indications: Kidney transplant prophylaxis, lymphangioleiomyomatosis

   • Formulations: Oral tablets, solution

   • Adverse Effects: Hyperlipidemia, delayed wound healing, thrombocytopenia

2. Everolimus

   • Indications: Transplant rejection, advanced renal cell carcinoma, hormone receptor-positive breast cancer

   • Benefit: Shorter half-life than sirolimus, allowing more flexibility in dosing

C. Selective Co-Stimulation Blockers

These agents block immune synapse signaling required for full T-cell activation.

1. Abatacept

   • Mechanism: CTLA-4 Ig fusion protein; blocks CD80/86 interaction with CD28 on T-cells

   • Indications: RA, psoriatic arthritis, juvenile idiopathic arthritis

   • Formulation: IV infusion or SC injection

   • Adverse Effects: Infusion reactions, increased risk of infections

D. JAK Inhibitors (Janus Kinase Inhibitors)

Selective inhibition of JAK enzymes (JAK1, JAK2, JAK3, TYK2) interferes with cytokine signaling involved in immune cell activation and proliferation.

1. Tofacitinib

   • Mechanism: JAK1 and JAK3 inhibitor

   • Indications: RA, psoriatic arthritis, ulcerative colitis

   • Formulation: Oral tablets

   • Boxed Warning: Increased risk of serious infections, thrombosis

2. Baricitinib

   • Mechanism: JAK1 and JAK2 inhibitor

   • Indications: RA, alopecia areata, COVID-19 (emergency use)

   • Adverse Effects: Herpes zoster reactivation, lipid abnormalities

3. Upadacitinib

   • Mechanism: Selective JAK1 inhibitor

   • Indications: RA, psoriatic arthritis, atopic dermatitis

E. Sphingosine-1-Phosphate (S1P) Receptor Modulators

These inhibit lymphocyte egress from lymph nodes, reducing peripheral immune cell availability.

1. Fingolimod

   • Indications: Relapsing MS

   • Mechanism: S1P receptor internalization → lymphocyte sequestration

   • Adverse Effects: Bradycardia, macular edema

2. Ozanimod, Siponimod

   • More selective for S1P1 and S1P5

   • Lower cardiovascular risks than fingolimod

F. IL-2 Receptor Antagonists

These monoclonal antibodies bind CD25 (IL-2Rα) on activated T-cells, inhibiting proliferation.

1. Basiliximab

   • Indications: Kidney transplant induction therapy

   • Formulation: IV

   • Adverse Effects: Generally well-tolerated

---

3. Pharmacokinetics and Dynamics

Agent	Route	T½ (hours)	Major Metabolism	Bioavailability	Distribution
Cyclosporine	Oral/IV	6–27	Hepatic (CYP3A4)	Variable (30%)	High tissue affinity
Tacrolimus	Oral/IV	12–18	Hepatic (CYP3A4)	~20–25%	Wide (crosses placenta)
Sirolimus	Oral	~60	Hepatic	~14%	Extensive
Tofacitinib	Oral	3–5	CYP3A4, CYP2C19	High	Moderate
Fingolimod	Oral	6–9 days	Phosphorylation	High	CNS-penetrant

4. Therapeutic Indications by Condition

Disease	Drug Classes Used
Kidney, liver, heart transplant	CNIs, mTOR inhibitors, IL-2 blockers
Rheumatoid arthritis	JAK inhibitors, abatacept, cyclosporine
Psoriasis	Cyclosporine, JAK inhibitors
Multiple sclerosis	S1P modulators (e.g., fingolimod, ozanimod)
Ulcerative colitis	Tofacitinib
Atopic dermatitis	Tacrolimus (topical), JAK inhibitors
Juvenile idiopathic arthritis	Abatacept

5. Adverse Effects

Common Class-Specific Effects

• Calcineurin inhibitors: Nephrotoxicity, neurotoxicity, hypertension

• mTOR inhibitors: Dyslipidemia, mouth ulcers, cytopenias

• JAK inhibitors: Infections, malignancy risk, thrombosis

• S1P modulators: Bradycardia, macular edema, hepatotoxicity

• Co-stimulation blockers: Infusion reactions, respiratory infections

Infection Risk

• Increased susceptibility to:

  • Herpes zoster (esp. JAK inhibitors)

  • Tuberculosis (screening required)

  • Opportunistic infections (e.g., CMV, pneumocystis)

---

6. Drug Interactions

Drug	Interactions	Clinical Relevance
Cyclosporine	CYP3A4 inhibitors (e.g., ketoconazole ↑), inducers (e.g., rifampin ↓)	Nephrotoxicity when combined with NSAIDs
Tacrolimus	Grapefruit juice (↑ tacrolimus levels)	Risk of toxicity, especially nephro- and neurotoxicity
Tofacitinib	CYP3A4 inducers (rifampin), inhibitors (fluconazole)	Dose adjustment necessary
Fingolimod	Beta-blockers, calcium channel blockers	Additive bradycardia
Sirolimus	Statins	Additive risk of myopathy

7. Contraindications and Precautions

• Pregnancy: Tacrolimus and cyclosporine may be used with caution; sirolimus and fingolimod are contraindicated

• Hepatic impairment: Dose adjustment may be required (especially for JAK inhibitors)

• Live vaccines: Should be avoided during treatment

• Cancer risk: Long-term use of immunosuppressants may increase malignancy risk (e.g., lymphomas, skin cancer)

---

8. Monitoring Parameters

Agent	Monitoring
Cyclosporine	Trough levels, serum creatinine, BP, LFTs
Tacrolimus	Trough levels, glucose, electrolytes, renal function
Sirolimus	Trough levels, lipids, CBC
Tofacitinib	CBC, LFTs, lipids, TB screening
Fingolimod	Heart rate, ophthalmology exam, LFTs, CBC

9. Selective vs. Non-Selective Immunosuppressants

Feature	Selective	Non-Selective
Mechanism	Specific immune pathways	Broad immune suppression
Examples	Tofacitinib, tacrolimus, abatacept	Corticosteroids, cyclophosphamide
Side Effect Profile	Targeted, lower infection risk	High incidence of systemic side effects
Monitoring	Requires molecular-level monitoring	Less specific
Use in Transplantation	First-line adjuncts	Often used for induction or flare-ups

10. Generic and Brand Name List

Generic Name	Brand Name	Class
Tacrolimus	Prograf, Protopic	Calcineurin Inhibitor
Cyclosporine	Neoral, Sandimmune	Calcineurin Inhibitor
Sirolimus	Rapamune	mTOR Inhibitor
Everolimus	Zortress, Afinitor	mTOR Inhibitor
Abatacept	Orencia	Co-stimulation Blocker
Tofacitinib	Xeljanz	JAK Inhibitor
Baricitinib	Olumiant	JAK Inhibitor
Upadacitinib	Rinvoq	JAK Inhibitor
Fingolimod	Gilenya	S1P Receptor Modulator
Ozanimod	Zeposia	S1P Receptor Modulator
Basiliximab	Simulect	IL-2 Receptor Antagonist