IMMUNOSUPPRESSANTS

Both acute and chronic rejection may result in hypertension. The former causes acute fluid retention and plugging of peritubular capillaries with inflammatory cells. This may progress to intimal swelling and medial necrosis and eventuate in ischemia secondary to endothelial proliferation and obliteration of small vessels. Chronic rejection, thought to be related to protracted humoral injury, results in obliteration of capillaries via the development of intimal hyperplasia. Cyclosporine has a vasoconstrictive effect which, through activation of the renin-angiotensin system, may lead to hypertension. RTAS is responsible for hypertension in 4% to 12% of renal allograft recipients. It responds well to percutaneous angioplasty. A careful trial of angiotensin-converting enzyme inhibitors may be diagnostic of RTAS. Recurrent disease such as membranoproliferative glomerulonephritis and focal glomerular sclerosis may result in significant hypertension in renal allograft recipients.

Both  acute  and  chronic  rejection  may  result  in hypertension. The former causes acute fluid retention and plugging of peritubular capillaries with inflammatory cells. This may progress to intimal swelling and medial necrosis and eventuate in ischemia secondary to endothelial proliferation and obliteration of small vessels. Chronic rejection, thought to be related to protracted humoral injury, results in obliteration of capillaries via the development of intimal hyperplasia. Cyclosporine has a vasoconstrictive effect which, through activation  of  the  renin-angiotensin  system,  may lead to hypertension. RTAS is responsible for hypertension in 4% to 12% of renal allograft recipients. It responds well to percutaneous angioplasty. A careful trial of angiotensin- converting enzyme inhibitors may be diagnostic of RTAS. Recurrent disease such as membranoproliferative  glomerulonephritis  and focal glomerular sclerosis may result in significant hypertension in renal allograft recipients.

Thalidomide

Adverse effects of tacrolimus:
 

• Nephrotoxicity

• Neurotoxicity (e.g., tremor, headache, motor disturbances, seizures)

• GI complaints

• Hypertension

• Hyperkalemia

• Hyperglycemia

• Diabetes

The major side effect of azathioprine is bone marrow suppression, including leukopenia (common), thrombocytopenia (less common), and/or anemia (uncommon).

The principal toxicities of Mycophenolate mofetil are gastrointestinal and hematologic.

Leflunomide is hepatotoxic and can cause fetal injury when administered to pregnant women.

Ref: Krensky A.M., Bennett W.M., Vincenti F. (2011). Chapter 35. Immunosuppressants, Tolerogens, and Immunostimulants. In L.L. Brunton, B.A. Chabner, B.C. Knollmann (Eds), Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12e.

Cefaclor is a second generation cephalosporin and is not known to have any immunosuppressive effects. Corticosteroids is having immunosuppressive properties.

• Monoclonal antibodies
• Fusion proteins

• Anti TNF alpha
• Daclizumab

Ans. is ‘a’ i.e., Calcineurin inhibitor

Ans. is ‘b’ i.e., IL2

• Cyclosporine enters target cells and bind to cyclophilin (an immunophilin).
• This cyclosporine-cyclophilin complex inactivates calcineurin 
• IL-2 trascripitan and proliferation of T cells.

Ans. is ‘c’ i.e., Multiple myeloma

o Cyclosporine is used in organ transplant (to prevent rejection) and autoimmune disorders (RA, psoriasis).

Ans. is ‘a’ i.e., Hypertension; ‘c’ i.e., Hirsutism

o Cyclosporin can cause nephrotoxicity (major side effect), hypertension, precipitation of diabetes (hyperglycemia), hirsutism, gum hyperplasia, hyperkalemia, hyperuricemia, heperlipedmia, hepatotoxicity and neurotoxicity.

Ans. is ‘a’ i.e., Amphotericin B

o All nephrotoxic drugs like aminoglycosides, Vancomycin, amphotericin B and NSAIDs enhance toxicity of cyclosporine.

Ans. is ‘b’ i.e., Tacrolimus

Tacrolimus

o It is a macrolide immunosuppressant agent.

o Its mechanism of action is similar to cyclosporine, i.e. inhibition of transcription of IL-2 and T-cell proliferation, but it binds to other immunophilin called FKBP (in contrast to cyclosporine which binds to cyclophilin). Subsequent steps are some, i.e. inhibition of calcineurin, which inhibits T cell activation.

o Tocrolimus is 10-100 times more potent than cyclosporine.

o It is also more toxic than cyclosporin..

o Adverse effects are nephrotoxicity (most common), neurotoxicity, hyperglycemia (DM).

Mechanism of nephrotoxicity —i Periglomerular afferent arteriolar vasoconstrication and reduced GFR.

o Note – Both cyclosporine and Tacrolimus can cause nephrotoxicity, hyperglycemia, and neurotoxicity —> should not be used together.

Ans. is ‘b’ i.e., Ototoxicity

Adverse effects of Tacrolimus

o Nephrotoxicity (most common and dose limiting)                                    o Neurotoxicity

o Hepatotoxicity                                                                                 o GI toxicity

o Alopecia                                                                                       o Hypertension

o Hematological toxicity (Leucocytosis, thrombocytopenia)                    o Endocrine (hyperglycemia, hyperlipidemia)

Ans. is ‘d’ i.e., Rifampicin

Tacrolimus is a highly nephrotoxic drugs.

o Other nephrotoxic drugs may precipitate tacrolimus induced nephrotoxicity, when used concomitantly. o Important nephrotoxic drugs that enhance tacrolimus induced nephrotoxicity are:

1. Aminoglycosides (e.g. gentamycin)             2. Vancomycin            3. Cisplatin

4. Amphotericin B                                     5. Cotrimoxazole       6. NSAIDs

Ans. is ‘d’ i.e., It can be safely administered with any nephrotoxic drug

Ans. is ‘c’ i.e., Hirsutism

Ans. is ‘b’ i.e., Cyclosporine

Ans. is ‘c’ i.e., It also inhibits calcineurin

Mycophenolate mofetil is a selective inhibitor of inosine monophosphate dehydrogenase. It does not inhibit calcineurin and is administered as an ‘add on’ therapy to a calcineurin inhibitor like cyclosporine.

Ans. is ‘c’ i.e., Mycophenolate inhibits purine synthesis via GMP dehydrogenase

o Mycophenolate inhibits purine synthesis via inosine monophosphate (IMP) dehydrogenase (not via GMP

dehydrogenase).

About other options

o Tacrolimus enters target cells and binds to FKBP. The complex then inhibits calcineurin response of the helper T cell to antigenic stimulation fails.

o Glucocorticoids bind cytosolic receptors and heat shock proteins, block transcription of IL-1, 2, 3, 6, IFN-y and TNF-cs

o Sirolimus complexes with FkBP -12 and then blocks p⁷° S⁶ kinase in the IL-2 receptors pathway for proliferation.

Answer is C (FK 506):

lmmunosuppression has customarily constituted triple therapy with : (NICE Guidelines)

1.       A calcineurin inhibitor (cvclosporin);

2.       An antiproliferative agent (azathioprine); and

3.       A corticosteroid (prednisolone)

However, a small number of treatment centers use a policy of initial monotherapy with a calcineurin inhibitor, adding in other agents if necessary.

Immunosuppressive therapy for renal transplantation in adults  Induction therapy

• Is a course of intensive immunosuppressive for about 2 weeks immediately post operatively (though often started immediately pre-operatively) with the aim of ‘switching off’ the immune system after transplantation to reduce the likelihood of accelerated rejection and acute rejection.
• It has also been used as a means of reducing exposure to calcineurin inhibitors in the early stages after transplantation when the graft may be particularly vulnerable to their nephrotoxic effects.

The term induction therapy has usually been linked with the use of the following agents:

–  The polyclonal antibodies antithymocyte immunoglobulin (ATG)

–  The antilymphocyte immunoglobulin (ALG), and

–  The monoclonal antibody muromonab-CD3 (OKT3)

Initial therapy

• Is the treatment given to all recipients (except where the donor is an identical twin) for 0-3 months after transplantation.
• Initial therapy is usually ‘triple therap^y‘, in which a clacineurin inhibitor (traditionally cyclosporine) is used as the ‘primary agent’ in combination with a corticosteroid (prednisolone) and azathioprine.
• Occasionally, dual therapy (cyclosporine plus costicositeroid) is used.

Maintenance therapy

• Is the treatment that patients receive long-term, throughout the duration of allograft survival
• Maintenance therapy is often identical to initial therapy (triple therapy) but at a reduced dosage because the transplanted kidney becomes immunologically more stable with increasing time.
• However, agents used in maintenance therapy may be altered in response to

– Development of acute rejection, severe infections or toxicity.

– Poor tolerability leading to non-adherence

Ans. D i.e. Immunomodulation

Thalidomide

• It is a synthetic derivative of glutamic acid (alpha-phthalimido-glutarimide) with teratogenic, immunomodulatory, anti-inflammatory and anti-angiogenic properties.
• Thalidomide acts primarily by inhibiting both the production of tumor necrosis factor alpha (TNF-alpha) in stimulated peripheral monocytes and the activities of interleukins and interferons.
• This agent also inhibits polymorphonuclear chemotaxis and monocyte phagocytosis.
• In addition, thalidomide inhibits pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), thereby inhibiting angiogenesis.

Ans. is ‘a’ i.e., Multiple myeloma

Clinical uses of thalidomide

• AIDS related aphthous ulcers
• AIDS related wasting syndrome
• Multiple myeloma and other solid tumours
• Prevention of graft versus host disease after transplantation
• Rheumatoid arthritis
• Ankylosing spondylitis
• Crohn’s disease and Bechet’s syndrome
• Erythema Nodusum Leprosum

Ans. is ‘a’ i.e., Anakinra

Ans. is ‘a’ i.e., Cephalosporin

Immunosuppressants

• These are drugs which inhibit cellular or humoral response or both
• These are mainly used in organ transplantation and autoimmune disease.

Ans. is ‘d’ i.e., Both ‘a’ and ‘c’

Ans. is ‘b’ i.e., Inhibitor of co-stimulation of T cells

Biologic response modifier (BRMs)

• Several recombinant proteins/monoclonal antibodies that bind and inhibit cytokines, especially TNFa or IL-1 have been used succesfully in autoimmune diseases like RA, IBD, psoriosis or scleroderma.

A) TNF-a inhibitors

• TNF-a plays a key role in the inflammatory cascade of RA by activating membrane bound receptors (TNFR, and TNFR₂) on the surface of T-cell and macrophages.
• TNF inhibitors mainly suppress macrophages and T cell function –> inflammatory changes in the joint regress and new erosion is slowed.
• Response is quicker than DMRADs.
• Though effective as monotherapy, they are generally added to methotrexate when response to the latter is not adqeuate or in rapidly progressing cases.
• Side effects are few, but susceptibility to opportunistic infections, including tuberculosis and pneumocystis pneumonia is increased. All are very expensive.

Etanercept

• It is a recombinant fusion protein of TNF – receptor and Fc portion of human IgG
• It is administered by S.C. injection.
• Infliximab
• It is a chimeral monoclonol antibody which binds and neutralizes TNF-a.
• It is given by i.v. route.
• It is indicated in RA, psoriotic arthritis, Crohn’s disease, Wegener’s granulomatosis and sarcoidosis.
• Adalimumab
• This recombinant monoclonal anti-TNF antibody.
• It is administered by S.C. route.

B) IL-1 antagonist

Anakinra

• It is a recombinant human IL-I receptor antagonist. 
• It is less effective than TNF inhibitors.
• It is administered by S.C. route.

C.T-cell costimulatory blockers

Abatacept

• It is a fusion protein that combines the extracellular domain of the molecule CTLA4 (CD 154) with the Fc portion of a human immunoglobulin.
• It interfere with the interactions between antigen presenting cells and T lymphocytes. Therefore, it affects early stages in the pathogenic cascade of event in RA.
• CTLA4 has high affinity for CD 28, when abatacept binds to CD28 on T cell surface, it prevents the second signal from being delivered, thus turning down the T cell response.
• Additional effects are decreasing the production of T cell derived cytokines including TNF.

D.  B-cell depleters

Rituximab

• B-cells are inflammatory cells with multiple functions in the immune response. The depletion of B cells has been shown to be effective in reducing signs and symptoms of RA and in slowing radiographic progression. o Rituximab is a chimeric monoclonal antibody that binds to the CD20 molecule on the B cell surface leading to the removal of B cells from the circulation.

Ans. is ‘a‘ i.e., IL-1 antagonist

• Anakinra is an IL-1 antagonist.
• It is used for some rare syndromes dependent on IL-1 production :

1. Neonatal – onset inflammatory disease
2. Muckle – Wells syndrome
3. Familial cold urticaria
4. Systemic juvenile – onset inflammatory arthritis
5. RA