Basics about immunosuppressive drugs in liver transplantation and protocols for immunosuppression in adult liver transplantation. Discusses the basic immunology of transplant, common drugs and protocols used in special scenarios in transplantation.
2. • Basics of Immunology
• Common drugs
• Protocols with evidence
3. The Immunology of Allogeneic
Transplantation
• Recognition of transplanted cells that are self or
foreign is determined by polymorphic genes
(MHC) that are inherited from both parents and
are expressed co-dominantly.
• Alloantigens elicit both cell-mediated and
humoral immune responses.
4. Recognition of Alloantigens
• Direct Presentation
• Recognition of an intact MHC molecule displayed by donor APC
in the graft
• Basically, self MHC molecule recognizes the structure of an
intact allogeneic MHC molecule
• Involves both CD8+ and CD4+ T cells.
5. Indirect Presentation
Donor MHC is processed and presented by recipient APC
Basically, donor MHC molecule is handled like any other foreign
antigen
Involve only CD4+ T cells.
Antigen presentation by class II MHC molecules.
6. Activation of Alloreactive T cells
and Rejection of Allografts
• Donor APCs migrate to regional lymph nodes
and are recognized by the recipient’s TH cells.
• Alloreactive TH cells in the recipient induce
generation of TDTH cell and CTLs then migrate
into the graft and cause graft rejection.
8. Role of Cytokines in Graft
Rejection
• IL – 2, IFN – , and TNF - are important mediators of graft
rejection.
• IL – α promotes T-cell proliferation and generation of T –
Lymphocytes.
• IFN - is central to the development of DTH response.
• TNF - has direct cytotoxic effect on the cells of graft.
• A number of cytokines promote graft rejection by inducing
expression of class – I or class – II MHC molecule on graft
cell.
• The interferon (α, and ), TNF – α and TNF - all
increases class – I MHC expression, and IFN - increases
class – II MHC expression as well.
10. Pre Csyclosporin Era
• Corticosteroids and azathioprine were used in
combination by Starzl et al. in his first 5
transplants.
• The majority of the Colorado series from 1963 to
1976 received corticosteroids, azathioprine, and
antilymphocyte globulin.
11. • 14 patients who underwent liver transplant were given cyclosporin as Immnosupressant
12. Transplant Proc. 1988 Feb;20(1 Suppl 1):498-504.
Experience in 1,000 liver transplants under cyclosporine-steroid therapy: a
survival report.
Iwatsuki S, Starzl TE, Todo S, Gordon RD, Esquivel CO, Tzakis AG, Makowka L,
Marsh JW, Koneru B, Stieber A, et al.
16. • Randomized Control Trial
• Total number of patient: 478 adults , 51 children
• Randomly assigned either tacrolimus (n=263)
and cyclosporin (n=266)
• Follow up period of one year
23. Mycophenylate Mofetil (MMF)/
Mycophenolic Acid (MPA)
• Inhibit the de novo purine nucleotide
synthesis via abrogation of the inosine
monophosphate dehydrogenase and the
production of guanosine nucleotides
• Leads to blockage of DNA replication in T
and B lymphocytes (can’t use salvage
pathways).
• MPA is a delayed release form of MMF
• Dosing –
• 1000-1500mg bid MMF or
• 360-720 BID MPA
24.
25.
26. Steroids
• Universally used as the initial immuno supression
• Variable dosage according to
• Philosophy
• Indication for transplantation
• Clinical risk factors
27.
28. MTOR Inhibitors
• Sirolimus
• Structurally similar to Tac ,binds to same target protein
• Different mechanism of action
• Complimentary action with TAC
• Better nephrotoxic profile
• Antiproliferative effect ? use in HCC
• 2002 (controversial) black box warning has affected use and
evidence
29.
30. Everolimus
• Derivative of Sirolimus
• Used as part of renal sparing regime
• FDA warning against use in first month
• Standard dose .75 mg twice daily
• Maintain drug levels 3-8 ng/ml
32. No ONE SIZE FITS ALL in immunosuppression
Factors determining regime
Indication for transplantation ( HCV, HCC, Autoimmune)
Co-morbidities ( renal, metabolic)
Peri-operative course
Indivisual philosophy
33. Renal Dysfunction
• Renal dysfunction is directly related to CNI
therapy
• More so after induction of MELD
• 3 strategies to spare the kidneys
• Induction with late introduction of CNI
• Low dose CNI with or without m-TOR inhibitors
• Non CNI based regimes
34. Group A- Tacrolimus >10ng/ml + steroids
Group B- Tacroliums<8ng/ml + steroids+mycofenolate
Group C- Daclizumab+delayed TAC (after day 5)+MMF
35. No difference in ACR,graft
survival, infectious
complications
Maximum renal injury
occurs in the early
post-transplant
period
36.
37. Timing of conversion is of paramount importance
Early conversion is more protective
Balance between graft safety and renal protection
Gradual withdrawal is probably better
38. Hepatitis C
• Steroids are implicated with high recurrence rates
• 3 strategies dealing with steroids
• Low dose steroids ( 5mg/day)
• Slow tapering of steroids (preferred)
• Steroid free immunosuppression
• Frequent changes in steroid levels are more deleterious
than absolute dosage
39. Hepatits C
• Cyclosporine vs Tacrolimus
• Cyclosporine was considered better
• Recent evidence suggests similar recurrence rates
• Most centres now use Tacrolimus
• MTOR inhibitors
• Suggested decreased fibrosis
• No great evidence to support
40. HCC
• Sirloins considered better because of anti-
proliferative action
• No high quality studies to support this claim
• No consensus regarding routine use in HCC
41. Metaanalysis of single centre retrospective
Observational studies
Lower recurrence rates with Sirolimus
Similar survival and complications rate
42. Metabolic risk
• Steroids responsible for higher incidence of
hypertension, hyperlipidemia,diabetes
• Tac higher rates of PTDM (post transplant diabetes
mellitus)
• Steroid free regimes are preferred for patients at
high risk
43. Autoimmune diseases
• Higher risk of rejection avoid under
immunosuprssion
• Prolonged use of steroids
• PBC ? cyclosporine better than TAC
44. Operational Tolerance
• ~20% can be weaned off immunosuppression in the long term
• Favourable factors
• Long duration after transplant
• Advanced age at transplantation
• Male gender
