Immunosuppression immunomodulation

1. DR. AHMED AKL, MD, PhD, FISN
CONSULTANT OF NEPHROLOGY & TRANSPLANTATION,
UROLOGY&NEPHROLOGY CENTER,
MANSOURA, EGYPT
ISN EDUCATIONAL AMBASSADOR
ISN EDUCATION AMBASSADORS PROGRAM Wednesday 14TH JUN 2017
IMMUNOSUPPRESSION
IMMUNOMODULATION

2. First Transplanted Patient in Mansoura 27 Mar 1976

3. HUMAN LEUKOCYTE ANTIGEN (HLA)

4. The Major Histocompatibility Complex (MHC)

5. History of Immunosuppression
• 1954: First successful renal transplant
• Identical twin donor w/o immunosuppression
• 1959: First successful allograft
• Non-identical twin
• Sublethal total body irradiation
• 1962: First successful unrelated allograft
• Azathioprine
• >1 yr survival
• 1963: Reversal of rejection with steroids
• 1967: First Heart Transplant—
died of rejection in several days

6. PHYSIOPATHOLOGY OF ISCHEMIA REPERFUSION
VIABILITY LOSS
ISCHEMIA
REPERFUSION
4-17% in 4 hours
73% in 3 hours

7. INNATE AND ADAPTIVE IMMUNE SYSTEM
Neutrophils -> proteases
-> ROS
-> pro-inflammatory cytokine
Macrophages -> pro-inflammatory
cytokine
NK cells -> perforin
DCs -> Pathogen-associated molecular proteins (DAMPs,
PAMPs).
-> Activation of the recipient T cells.
PHYSIOPATHOLOGY OF ISCHEMIA REPERFUSION

9. ACTIVATION

10. TRANSPLANTATION IMUUNOLOGY
Regulatory T cells Effector T cells

11. THYMUS … T CELL REGULATION

12. EXPERIMENTAL MODELS

13. TOLERANCEREJECTION
EXPERIMENTAL MODELS

14. REJECTION TOLERANCE
IN EXPERIMENTAL MODELS

15. IN HUMANS

17. Wood And Sakaguchi, 2003
Regulatory T Cells: Potential To Facilitate Specific
Unresponsiveness In Transplantation

19. PUBLISHED CLINICAL TRIALS

20. ONGOING UNPUBLISHED CLINICAL TRIALS

21. General Principle of Immunosuppression
• Primary immune responses are more easily repressed than
secondary (memory)
• Suppression is more likely to be achieved if therapy is begun before
exposure to the immunogen
• Different immunosuppressants have different effects on different
immune reactions and mediators

22. CATEGORIES OF AGENTS
• INDUCTION AGENTS [PROTEIN DRUGS]
• Monoclonal or polyclonal antibodies
• Administered intravenously immediately following surgery
• MAINTENANCE AGENTS [SMALL-MOLECULE DRUGS]
• Prednisone
• CNIs form the cornerstone of immunosuppressive therapy
• Antiproliferative agents: Cellcept, Imuran, Rapamune
• Triple agents / withdrawal / avoidance / conversion

23. INDUCTION AGENTS

25. INDUCTION AGENTS
• Muromonab (OKT3)
• Equine polyclonal ATG (ATGAM)
• Rabbit polyclonal ATG (Thymoglobulin)
• Basiliximab (Simulect) - Daclizumab (Zenapax)
• Alemtuzumab (Campath-1H)

26. •1ST dose given in OR
•Dose: 1.5 mg/kg
•Adverse effects: cytokine release syndrome (fever,
chills, arthralgia), leucopenia, thrombocytopenia
•Premedication: Tylenaol, Benadryl, Hydrocortisone
•Also effective in treating rejection
THYMOGLOBULIN

27. Anti-IL-2 Receptor Antibodies
• BASILIXIMAB (SIMULECT)
• Chimeric antibody (75% human, 25% mouse)
• Dosing: 20 mg i.v. pre-op and POD# 4
• DACLIZUMAB (ZENAPAX)
• Humanized (95% human, 5% mouse)
• Dosing: 1 mg/kg pre-op and q 2 w for total 6 doses
• NOT EFFECTIVE FOR TREATING REJECTION

28. MAINTENANCE
IMMUNOSUPPRESSION

29. CNI: Dosing
• CYCLOSPRINE (NEORAL, GENGRAF, SANDIMMUNE)
• Initial dosing: 8-10 mg/kg/day
• Maintenance: 2-6 mg/kg/day
• TACROLIMUS (PROGRAF)
• Initial dosing: 0.15 mg/kg/day
• Maintenance:0.05-0.15 mg/kg/day

30. TACROLIMUS (PROGRAF): MONITORING
Low risk Mod Risk High risk
0-6 m 6-12 ng/ml 8-12 ng/ml 8-15 ng/ml
6-12 m 5-8 ng/ml 5-10 ng/ml 6-12 ng/ml
> 12 m 4-8 ng/ml 5-10 ng/ml 6-12 ng/ml
S Hariharan. Am J Kidney Dis. 2006. 47(S2):S22-S36.

31. MODIFICATION CONJUGATION
Iarbovici D. Single blood test might predict drugs’ effects on patients. J NIH Res 1997;9:34-45.
Drug Metabolism

32. Drug Metabolism
Iarbovici D. Single blood test might predict drugs’ effects on patients. J NIH Res 1997;9:34-45.
ANTIPORTER ACTIVITY
 Is an important factor in the first pass metabolism
of pharmaceuticals.
 The antiporter is an energy-dependent efflux
pump, which pumps DRUG out of a cell, decreasing
the intracellular concentration.

33. GENETIC POLYMORPHISM

34. PERSONALIZED MEDICINE

35. CNI SIDE EFFECTS
Event Comments
Hepatotoxicity  Liver function should be monitored at regular
intervals
Cardiovascular
 Hypertension
 Hypercholesterolemia
 Fewer tacrolimus-treated patients require
antihypertensive medications
 Tacrolimus’ impact on lipid levels is less than
that seen with cyclosporine
Glucose intolerance  Recent studies indicate little differences
between tacrolimus and cyclosporine
Neurotoxicity
 Tremor
 Headache
 Insomnia
 Paresthesia
 Seen more often with tacrolimus and
generally improve with dose reduction

36. CNI SIDE EFFECTS
Event Comments
Cosmetic side effects
 Gingival hypertrophy
 Hirsutism
 Alopecia
 Use of steroids may exaggerate
development
 Gingival hypertrophy and hirsutism are
associated with cyclosporine
 Calcium channel blockers can exacerbate
gingival hypertrophy
 Alopecia can occur with tacrolimus
Malignancy
 Skin cancers
 Cervical cancer
 Lymphoproliferative
disorders
 Incidence appears to be a function of
overall amount and duration of
immunosuppression rather than any specific
agent

37. CNI
More with Tacrolimus More with Cyclosprin
Neurologic SE Hypertension
GI side effects Hyperlipidemia
PTDM
Alopecia Hirsutism
Hypertrophic cardimyopathy
in children
Gingival hyperplasia

38. Metabolic Interactions That Increase CNI Levels
• CALCIUM CHANNEL BLOCKERS
• Verapamil
• Diltiazem
• Amlodipine
• Nicardipine
• ANTIFUNGAL AGENTS
• Ketoconazole
• Fluconazole
• Itraconazole
• Clotrimazole
• Metronidazole
• IMMUNOSUPPRESSANTS
• Sirolimus
• GLUCOCORTICOIDS
• Methylprednisolone
• ANTIBIOTICS
• Erythromycin
• Clarithromycin
• Josamycin
• Ponsinomycin
• Azithromycin
• PROTEASE INHIBITORS
• Saquinavir
• Indinavir
• Nelfinavir
• Ritonavir
• FOODS
• Grapefruit
• Grapefruit juice

40. Metabolic Interactions That Decrease CNI Levels
• ANTITUBERCULOSIS DRUGS
• Rifampin
• Rifabutin
• Isoniazid
• ANTICONVULSANTS
• Barbiturates
• Phenytoin
• Carbamazepine
• HERBAL PREPARATIONS
• Saint John’s wort
• ANTIBIOTICS
• Nafcillin
• IV trimethoprim
• IV sulfadimidine
• Imipenem
• Cephalosporines
• Terbinafine
• Ciprofloxacin
• OTHER DRUGS
• Ticlopidine
• Octreotide
• Nefazodone

41. Non-metabolic Interactions With CNIs
Drug Type Comments
 NEPHROTOXIC AGENTS
 NSAIDs
 Vancomycin
 Ganciclovir
 Aminoglycosides
 Monitor renal function
 NSAIDs may have increased nephrotoxicity
with hepatic impairment
 POTASSIUM-SPARING
DIURETICS
 Hyperkalemia has been reported
 ANTACIDS  Magnesium and aluminum antacids may
inhibit absorption of CNIs
 If necessary, should be taken 2 hours after
CNI dose
 HMG-CoA reductase inhibitors
(statins)
 Increased risk of rhabdomyolysis, bone
marrow suppression

42. Dosing of Adjuvant Agents
Agent Daily Dose Monitoring
Azathioprine 1-3 mg/kg qd None available
MMF (Cellcept) 750 mg-1.5 g bid MPA:1.6 – 2.75 mg/L*
Sirolimus 2-5 mg qd 5-15 ng/mL (whole blood
trough level)
Corticosteroids 5-10 mg qd None available
*Borrows R, et al. Am J Transplant 2006(6):12-128

43. Side Effects of Antiproliferative Agents
Drug and Side Effects Clinical Implications
 Azathioprine
 Leukopenia
 Anemia
 Thrombocytopenia
 Hepatitis
 Cholestasis
 Pancreatitis
 Complete blood counts should be
performed regularly to monitor for
hematologic side effects
 MMF
 Leukopenia
 Anemia
 Thrombocytopenia
 Diarrhea
 Nausea
 Bloating dyspepsia
 Vomiting
 Esophagitis
 Gastritis
 Complete blood counts should be
performed regularly to monitor for
hematologic side effects
 GI side effects are more common
when dose exceeds 1 g bid and
respond to dose reduction or more
frequent administration of smaller
doses

44. Drug Interactions With Antiproliferative Agents
Drug Interactions
Azathioprine  Coadministration with ganciclovir, ACE inhibitors,
carbamazepine, clozapine, or cotrimoxazole can
lead to the exacerbation of hematologic toxicity
 Allopurinol is contraindicated, as concomitant
administration can lead to life-threatening
myelosuppression
MMF  Co-administration with ganciclovir, ACE inhibitors,
carbamazepine, clozapine, or co-trimoxazole can
lead to the exacerbation of hematologic toxicity
 Administration with tacrolimus may potentiate GI
side effects

45. Myfortic
•Enteric-coated MMF
•Intended to reduce GI side effects but has not been
proved in clinical trials
•Dose equivalent
• 180 mg Myfortic = 250 mg MMF

46. Mycophenolate v. Azathioprine
•Several studies, particularly some initial pivotal reports,
found that acute rejection rates were lower with
mycophenolate. However, these studies may be flawed.
•Given current evidence, azathioprine and mycophenolate
mofetil appear to be similar in terms of acute rejection
rates and long-term allograft survival rates.

47. Mycophenolate v. Azathioprine
• MYSS TRIAL
• 336 patients undergoing a deceased donor renal transplant
• Randomly assigned to mycophenolate mofetil or azathioprine
• Both groups also receiving cyclosporine microemulsion and
corticosteroids. Corticosteroids were continued for the first six
months (phase A), after which they were slowly withdrawn and
patients were followed for another 15 or more months (phase B).
Remuzzi G. et al. Lancet 2004 Aug 7;364(9433):503-12.

48. Mycophenolate v. Azathioprine
MYSS Follow-up Study
Remuzzi G. et al. J Am Soc Nephrol. 2007 June; 18: 1973–1985.

49. Practical Considerations
• Can take with food/meds
• GI symptoms responsive to change in dose
• Switch to AZA if not tolerated
• Suspend/change dose for WBC<3.5
• Generic ok
Mycophenolate:

50. mTOR Inhibitor
•Dosage: 2-5 mg qd
•Level: 5-15 ng/mL (whole blood trough level)
Sirolimus (Rapamune / Rapamycin)

51. SIDE EFFECTS OF SIROLIMUS
Drug and Side Effects Clinical Implications
 Sirolimus
 Hypercholesterolemia
 Hypertriglyceridemia
 Hypertension
 Rash
 Leukopenia
 Anemia
 Thrombocytopenia
 Interstitial pneumonitis
 Delayed wound healing
 Mouth ulcers
 Proteinuria
 Edema
 AZOOSPERMIA
 Pneumonitis occasionally
resolved in discontinuation of
sirolimus

52. Drug Interactions With Sirolimus
• As sirolimus is metabolized by the same pathway as the
CNIs (P-450 3A4), interactions are the same
• Sirolimus has been shown to raise blood levels of
cyclosporine and MMF
• Sirolimus should be administered 4 hours after
cyclosporine or tacrolimus
• Sirolimus blood levels are raised by cyclosporine
• Proper monitoring is advised

53. Steroids
• Prednisone
• Methylprednisone
• Decreased activity with anti-TB and anti-seizure medications
• Increased activity with estrogen, OCP, erythromycin

54. Side Effects of Corticosteroids
Drug and Side Effects Clinical Implications
 Corticosteroids
 Acne
 Cushingoid facial appearance
 Hirsutism
 Mood disorders
 Hypertension
 Glucose intolerance
 Cataracts
 Osteoporosis
 Growth retardation in children
 May potentiate adverse
events of CNIs

55. Practical Considerations
• Wean as quickly as condition allows
• Divide dose when >20mg daily
• Infection prophylaxis when >10mg daily
• Give with food
• Not all weight gain is steroid-induced
• Encourage weight bearing exercise for bone health
STEROIDS

57. Tailoring Drug Regimens
• REFRACTORY TRANSPLANTED GRAFT REJECTION
• Changing from cyclosporine to tacrolimus has proven successful in
reversing rejection
• CARDIOVASCULAR DISEASE
• High blood pressure and high cholesterol may be lowered with changes
from cyclosporine to tacrolimus
• High cholesterol may also be lowered by replacing sirolimus with MMF
• Diabetes
• De novo presentation of diabetes may improve with lowering of steroid
dose.
• Rarely, patients switched from tacrolimus to cyclosporine may see
improvements of glucose metabolism

58. • Hirsutism
• Changing from cyclosporine to tacrolimus generally reverses hirsutism
• Gingival hyperplasia
• Replacing cyclosporine with tacrolimus can alleviate gingival hyperplasia
• Withdrawing calcium channel blockers may also lead to improvements in
gingival tissue
• Tremor
• If dose reduction of the CNI does not stop tremor, consider switching to
the alternate therapy
• Gout
• Convert azathioprine to MMF if allopurinol must be used
Tailoring Drug Regimens

59. DEFICIENCIES WITH IMMUNOSUPPRESSIVE THERAPY
• Patient’s compliance and adherence
• Side effects of long-term exposure
• Long-term comorbidities induced by these agents
• Need to continue these agents for life
• Inability to induce tolerance

60. PROTOCOLS

61. CONCLUSION
• Understanding proper dosing and monitoring becomes especially
critical when comorbid conditions are involved
• Some side effects are inherent with a suppressed immune system;
others occur as the result of specific agents.
• Experimental drug protocols that eliminate or withdraw steroids
and CNIs remain untested in the long term and must be eyed with
caution.
• Patient education regarding compliance should be ongoing
throughout the life of the transplant

62. THE UROLOGY & NEPHROLOGY CENTER,
MANSOURA