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Management 
of 
Liver Transplant Rejection 
Dr Palepu B Gopal 
MD,FRCA,CCST,FICCM,FCCM 
Consultant 
Critical Care Medicine 
Hyderabad
Complications Of Organ 
Transplantation 
1- Rejection 
2-Malignancy
Causes of Allograft Failure 
 Primary Nonfunction – slightly more common in 
Living Donors 
 Vascular Complications – 10% of patients 
 Hepatic Artery Thrombosis/Stricture 
 Portal Vein Thrombosis/Stricture 
 Hepatic Vein Thrombosis/Stricture 
 Biliary Complications – 
 Donors after Cardiac Death 
 Living Donors 
 Anastomotic vs nonanastomotic strictures
Causes of Allograft Failure- 
Rejection 
 Antibody Mediated Rejection – hours to 
days 
 10-20% Acute Rejection 
 Risk 1st 3months>1st year>subsequent 
years 
 Chronic Rejection – a primary RF is prior 
episodes of Acute Rejection. 
 Acute vs Chronic – 
○ time course 
○ pattern of liver enzyme abnormalities 
○ response to therapy
Transplant Rejection – Issues for Critical Care 
Single organ dysfunction of organ under Rejection 
MOF related to single organ dysfunction 
Extended Immunosuppression 
Infections 
Drug Interaction 
Toxicity 
Sepsis and MOF 
Drug Toxicity 
Renal Failure
Immunology and 
Etiopathogenesis 
of Rejection
Late Hepatic Allograft Dysfunction : Wiesner et al. Liver Transpl 
2001 
Rejection 
Causes reduction or withdrawal of immunosuppressants, 
erratic absorption 
poor compliance 
Poor prognosis Rejection in Hep C Tx 
High risk for Ac rejection Age less than 30 years 
Tx for an autoimmune liver disease 
ALD 
Child’s A at the time of Tx 
Interferon for Hep C 
Low Risk for Ac Rejection Age more than 60 years 
Tx for Alcoholic liver disease 
Child’s class C at the time of Tx 
Immunospp. Regimen high-dose steroids response 80% 
Others require antilymphocyte therapy 
Less rejection with tacrolimus than 
cyclosporine regimens 
14% rejection rate with Tacro and 
sirolimus combination
Late Hepatic Allograft Dysfunction 
Russell H. Wiesner and K.V. Narayanan Menon 
Liver Transplantation, Vol 7, No 11, Suppl 1 2001
Types of Transplant 
Autograft is self-tissue transferred from one 
body site to another in the same individual. 
Isograft is tissue transferred between 
genetically identical individuals. 
Allograft is tissue transferred between 
genetically different members of the same 
species. 
Xenograft is tissue transferred between 
different species
Immunology of Transplant Rejection 
Components of the Immune system involved in graft Rejection : 
1) Antigen presenting cells – 
○ Dendritic cells 
○ Macrophages 
○ Activated B Cells 
2) B cells and antibodies – 
○ Preformed antibodies 
○ Natural antibodies 
○ Preformed antibodies from prior sensatization 
○ Induced antibodies 
3) T cells 
4) Other cells – 
○ Natural killer cells 
○ T cells that express NK cell – associated Markers 
○ Monocytes/Macrophages
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.
 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.
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.
Activation of Alloreactive T 
cells and Rejection of 
Allografts 
(SENSATIZATION) 
Passenger leukocyte 
Class II MHC. 
antigen 
H H T T 
IL  2 
H T H T 
Donar kidney 
CTL 
CTL 
T DTH DTH T 
EFFECTOR LYMPH NODE
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.
Effector Mechanisms of Allograft 
Rejection - Types 
 Hyperacute Rejection 
 Acute Rejection 
 Chronic Rejection
Hyperacute Rejection 
 Characterized by thrombotic occlusion of the graft 
 Begins within minutes or hours after anastamosis 
 Pre-existing antibodies in the host circulation bind 
to donor endothelial antigens 
 Activates Complement Cascade 
1.Preformed Ab 
2.complement activation 
3.neutrophil margination 
4.inflammation, 
5.Thrombosis
Acute Rejection 
 Vascular and parenchymal injury mediated by T 
cells and antibodies that usually begin after the 
first week of transplantation if there is no 
immunosuppressant therapy 
 Incidence is high (30%) for the first 90 days 
 T-cell, macrophage 
and Ab mediated, 
 myocyte and endothelial 
damage, 
 Inflammation
Chronic Rejection 
 Occurs in most solid organ transplants 
 Heart 
 Kidney 
 Lung 
 Liver 
 Characterized by fibrosis and vascular abnormalities with 
loss of graft function over a prolonged period. 
Macrophage – T cell mediated 
Concentric medial hyperplasia 
Chronic DTH reaction
Graft vs. Host Disease 
 Caused by the reaction of grafted 
mature T-cells in the marrow inoculum 
with alloantigens of the host 
 Acute GVHD 
 Characterized by epithelial cell death in the 
skin, GI tract, and liver 
 Chronic GVHD 
 Characterized by atrophy and fibrosis of one 
or more of these same target organs as well 
as the lungs
Clinical Picture and 
Diagnosis
Wyatt (2010) Histopathology 57, 333–341 
Biopsy
Causes of Liver Test Abnormalities in 
Asymptomatic Recipient 
Allograft parenchymal damage 
Immune-mediated disease 
rejection and de novo AIH) 
Recurrent Liver disease 
Drug toxicity 
immunosuppressive drugs 
Alcohol and other toxins 
De novo infection 
Bacterial, Viral (de novo HBV and 
HCV) 
Space-occupying lesion 
De novo or recurrent NAFLD 
Biliary damage 
Biliary strictures , anastomotic strictures, 
Hep A Stricture 
Biliary stones/cast syndrome 
Recurrent PSC 
Vascular disease 
Hepatic artery thrombosis 
Portal or hepatic vein thrombosis 
Metabolic disease of Graft 
Gilbert’s syndrome 
Nonhepatic disease 
Hemolysis – 
indirect bilirubin 
Bone disease 
raised ALP 
Nonhepatic disease 
Celiac disease 
Diabetes
Late Hepatic Allograft Dysfunction 
Russell H. Wiesner and K.V. Narayanan Menon 
Liver Transplantation, Vol 7, No 11, Suppl 1 (November), 2001 
Time to first rejection episode among adult liver 
recipients who rejected following liver transplantation.
Prevention 
and 
Management 
of Rejection
Episodic Treatment of 
Rejection 
Immunotherapy is truly a treatment 
that delays the inevitability of graft 
rejection. 
Rejection Episodes can be treated by 
the one of the following treatments: 
 Corticosteroid 
 Polyclonal and Monoclonal Antibodies 
 Antiproliferatives 
Alternative Therapies 
Xenotransplantation 
Tissue Engineering 
Stem Cell Research 
Induction of Tolerance
Recommendations for Prevention and Tt of Rejection 
 Immunosuppressants recipients should be prescribed and 
monitored by expertis in that area 
The choice of agents is multi-factorial, and no one regimen 
can be recommended for any patient (grade 2, level A) 
Reviewed at least every 6 months and modified as required 
Goal of minimizing long term toxicities (grade 1, level B). 
Rejection can be diagnosed only on the basis of liver biopsy 
classified according to Banff criteria (grade 1, level A) 
Long-Term Management of the Successful Adult Liver Transplant: 2012 Practice 
Guideline by the ASSLD and AST. Michael R. Lucey: 
LIVER TRANSPLANTATION 19:3-26, 2013
Clinical Immunosuppression 
Two types of immunosuppression are used in transplantation: 
Induction and Maintenance immunosuppresion 
Adverse side-effects that include 
high incidence of opportunistic infection 
transplant-related malignancies in patients 
Major goal of immunosuppression 
Identify the optimal balance of therapy 
Effective prevention of allograft rejection 
Minimized Adverse effects, infection & malignancies
A cute cellular rejection (ACR) is a very common 
event that occurs in utpo 70% of orthotopicl iver 
transplant (OLT) recipients within the first year.l The 
highest incidence is around 7 to 10 days posttransplantation. 
ACR occurs i n 10% to 70% of patients, 
depending on the primary immunosuppression used, 
the indication for the transplantation, and the definition 
of rejection. 
histologic features of portali nfiltrate and endotheliitis, which suggest 
mild 
ACR, but without biochemical graft dysfunction, often 
resolves without adjuvant immunosuppression.3 
So, liver biopsies should be delayed until patients 
develop biochemical graft dysfunction, unexplained 
fever, or other surrogate markers of rejection. 
Liver Transplantation, Vol8, No 12 (December), 2002:pp 1147-1 153
Immunosuppressants
Timeline for the introduction of immunosuppression 
medications. 
Immunosuppression in Liver Transplantation. Post et al. LiverTransplantation, Vol 11, No 11,2005: pp 
1307-1314
Immunosuppressive Agents 
Immunosuppression can be achieved in by 
1. Surgical ablation 
2. Total Lymphoid Irradiation 
3. Immunosuppressive drugs
Immunosuppressive Drugs 
Three main immunosuppressant drugs 
 Cyclosporins act by inhibiting T-cell activation, thus 
preventing T-cells from attacking the transplanted 
organ 
 Azathioprines disrupt the synthesis of DNA and RNA 
and cell division 
 Corticosteroids such as prednisolone suppress the 
inflammation associated with transplant rejection
Organ Specific Immunosuppressant 
Classification 
 Kidney transplants 
○ Basiliximab in combination with cyclosporin and 
corticosteroids 
 Kidney transplants 
○ Daclizumab in combination with cyclosporin and 
corticosteroids 
 Kidney, liver and heart transplants 
○ muromonab CD3 (Orthoclone OKT3) along with cyclosporin 
 Liver transplants Tacrolimus 
○ under study for kidney, bone marrow, heart, pancreas, 
pancreatic island cell, and small bowel transplantation.
Induction Therapy 
Def: prophylactic application of periop antibodies in 
addition to baseline immunosuppression. (immediate 
posttransplant) 
The goal : induce hyporesponsiveness in the organ 
recipient toward the transplanted organ in order to 
prevent early post-transplant rejection 
Only T cells are inhibited and the rest of the patient's 
immune system would remain fully functional 
Agents: Earlier nonspecific polyclonal antibodies 
Today, however, murine monoclonal anti-lymphocyte 
antibodies, such as OKT3, are often used 
Antimicrobials are a necessary component
Maintenance immunosuppression 
Drugs administered to maintain immuno-suppression 
once recipients have recovered 
from the operative procedure. 
Agents are either 
Biological Monoclonal and polyclonal 
antibodies 
Generally used in induction 
protocols 
Nonbiological agents 
Mainstay of maintenance protocols. 
corticosteroids 
azathioprine 
cyclosporines
Maintenance Therapy 
Maintenance immunosuppression refers to the classic 
combination therapy (known clinically as Triple Therapy) to 
which transplant recipients usually adhere for the rest of their 
lives. 
The Combination includes 
 a corticosteroid 
 a calcineurine inhibitor 
 an antiproliferative 
The Goal Balance between underimmunosuppression and 
overimmunosuppression 
Consider potential interactions
Calcineurin Inhibitors (CNIs) 
Calcineurine (cytokines activator ) Inhibitors are used in 
maintenance immunosuppression. 
Cyclosporin A From fungus Tolypocladium inflatum 
selective suppression of CMI via inhibition 
of T-cell activation 
standard formulation (Sandimmune) emulsion 
depends on bile flow, GI motility & food 
intake 
Unpredictable bioavailability 
Microemulsion in lipophilic solvent (Neoral) 
Predictable bioavailability 
Drug Interactions 
Nephrotoxicity – up to 20% post OLT Renal failure 
Neurological manifestations – 10-28% 
hyperkalemia, hypomagnesemia, hyperglycemia 
Hypertension, gingival hyperplasia and hirsutism 
Immunosuppression in Liver Transplant. Post et al. LiverTransplantation, 2005
Rejection cc 2014 jaipur
Tacrolimus 
From fungus Streptomyces tsukubaensis in Japan 
Tacrolimus is a microlide antibiotic 
100 times more potent than CyA 
Inhibits calcineurin 
TAC absorption uninfluenced by presence of bile 
Lower first year rejection rate better with TAC compared to 
CyA 
Hepatitis C infected patients on TAC have longer graft 
survival Immunosuppression in Liver Transplantation. Post et al. LiverTransplantation, Vol 11, 
No 11,2005: pp 1307-1314
Common Side Effects of Tacrolimus 
Post-transplant diabetes mellitus 
Nausea, vomiting, diarrhea 
Hyperkalemia 
Tremor 
Hypertension 
Hypomagnesemia 
Headache 
Renal dysfunction
Sirolimus 
 Binds to same immunophilin as Tac (FKBP12) but with a 
different mechanism of action 
○ blocks response of T and B Cell Activation by cytokines 
 Theoretical (lab based) antineoplastic and antifungal 
effects. 
 Early excitement about renal protective effect- subsequent 
studies have not confirmed this 
 Black Box warning – possible increased risk of Hepatic 
Artery Thrombosis in immediate post-OLT setting 
 Recent study of switch from CNI to SRL suggests possible 
increased mortality 
 Currently using in those intolerant to CNIs, and in some 
patients for theoretical antineoplastic and renoprotective 
actions 
Hepatology. 2010 Oct;52(4)
Sirolimus – Adverse Effects 
• Anemia 
• Hypercholesterolemia 
• Hypertriglyceridemia 
• Leukopenia 
• Hyperlipidemia 
• Interstitial lung disease 
• Thrombocytopenia 
• Peripheral edema 
• Wound dehiscence 
• Hepatic Artery Thrombosis
Rejection cc 2014 jaipur
Corticosteroids 
Prednisone and Methylprednisolone 
Corticosteriods Maintenance immunosuppression 
Teatment of acute rejection 
Diffuse into cells and bind to specific 
cytoplasmic receptors progress to the 
nucleus, inhibit the transcription of the genes 
of the cytokines 
Block T cell, APC and Macrophase cytokines 
IL-1, IL-6, IL-2, INF-γ , and TNF-α 
Non-specific anti-inflammatory agents 
acutely reduce lymphocytes & monocytes 
Pretransplant bolus dose of methylprednisolone 500 to 1,000 mg, 
followed by rapid taper over next few weeks to minimal dose, i.e., 
25-50 mg/day.
Common Side Effects of Corticosteroids 
Hypertension 
Mental status changes 
Lipid abnormalities 
Impaired wound healing 
Hyperglycemia 
Cushingoid syndrome 
Ulcers 
Myopathy 
Osteoporosis 
Fluid retention 
Cataracts
Antiproliferative Agents / Antimetabolites 
Mycophenolate Mofetil, Azathioprine, Sirolimus 
Antiproliferative Block the proliferative phase of ACR 
Maintenance immunosuppression 
Treatment of rejection 
Azathioprine Mercaptopurine derivative & antagonises purine metabolism 
Significant myelosuppression and hepatotoxicity 
Use decreased dramatically 
Mycophenolate mofetil and Mycophenolic acid 
Mycophenolate Mofetil (MMF) 
Rapidly hydrolyzed in the blood to its active form: MPA 
MPA inhibits enzyme IMPDH in the pathway of purine biosynthesis 
Activated lymphocytes are selectively inhibited 
Nausea, vomiting, diarrhea, Pancytopaenia
Antibody Induction 
 Antithymocyte Globulin – induction/rejection. 
 Polyclonal antilymphocyte globulin – multiple 
epitopes on T cell receptor – lead to apoptosis 
of T-cells 
 ATGAM (of equine origin) 
 Thymoglobulin (of rabbit origin) 
 Monoclonal anti T-Cell antibodies – 
induction/rejection 
 Muromonab-CD3 (OKT3) – binds CD3 Antigen 
on T-Cell receptor – inactivates adjacent T-Cell 
– leads to rapid drop in T-Cells 
 IL-2 Receptor Antibodies – induction 
 Basiliximab (Simulect) 
 daclizumab (Zenapax).
Monoclonal Antibodies 
Muromonab-CD3 (Orthoclone OKT3®) 
Used in LTx in 1987 for prophylaxis against acute cellular rejection 
and later to reduce CNI exposure and treatment of steroid-resistant rejection. 
OKT3 use today is much lower, with many centers preferring treatment 
regimens 
for acute cellular rejection to increasing TAC blood levels and then adding 
corticosteroid boluses if rejection is still present 
Daclizumab (Zenapax®) 
Interleukin-2 Receptor Antagonist (Basiliximab, Simulect®) 
Monoclonal Antibodies are used in early rejection prophylaxis and treatment 
of rejection. 
Monoclonal antibodies are antigen-specific immunosuppressants that will 
reduce immune response to alloantigens of the graft while preserving the 
response to alloantigens to unrelated antigens. 
These agents are specific to blocking T-cell activation, resulting in rapid 
depletion of T cells from the circulation by binding of antibody coated T cells 
to Fc receptors on phagocytic cells. The most recently FDA approved 
monoclonal antibodies are the IL-2 receptor antagonists genetically 
engineered to possess both human and murine antibody sequences. The 
chimerization of these antibodies is an attempt to decrease the 
immunogenicity of the agent. Other monoclonal antibody-based drugs are
Monoclonal Antibodies 
Muromonab-CD3 is the first type of murine monoclonal antibody directed 
against the ε chain of the CD3 molecule (an integral part of the T Cell 
Receptor complex) and modulates the receptor and inactivates T-cell 
function blocking both naïve T cells and CTLs. This results in rapid depletion 
of T cells from circulation and cytokine release. This antibody is used to treat 
acute rejection and steroid resistant rejection. 
Basiliximab is a chimeric (70% human and 30% murine) monoclonal 
antibody utilized in the prevention of acute organ rejection. This monoclonal 
antibody has a specificity and high affinity for the α subunit of the interleukin 
(IL)-2 receptor (IL-2Rα, also known as CD25 or Tac) preventing IL-2 from 
binding to the receptor on the surface of activated T cells. By acting as an 
IL-2Ra antagonist, Basiliximab inhibits IL-2-mediated activation and 
proliferation of T cells, the critical step in the cascade of cellular immune 
response of allograft rejection. Therefore, Basiliximab has a long half-life of 
approximately 7-12 days and saturates the IL-2 receptor for up to 59 days. 
Due to its high percentage of humanization in its antibody sequences the 
occurrence and acuteness of adverse effects is significantly lower when 
used with standard immunotherapy.
Monoclonal Antibodies 
Muromonab – CD3 Daclizumab is a similar agent to Basiliximab, but is a more 
humanized IgG monoclonal antibody (90% human and 10% murine). It also binds to 
and inhibits the α-subunit of IL-2 receptor and thus works in a manner similar to 
Basiliximab. Daclizumab is able to saturate the IL-2 receptor twice as long as 
Basiliximab. Because it is more humanized, there are less side effects associated 
with Daclizumab. 
Side Effects – HAMA One of the major problems affecting monoclonal therapy is the 
side effects associated with the HAMA (Human anti-Murine Antibody) response and 
serum sickness. These are both directly caused by the structure of the antibodies. 
Laboratories routinely use murine antibodies as a starting point for monoclonal 
antibodies. 
A counteractive measure includes humanizing (or chimerizing) the antibody. Because 
the only immunologically offensive portion of the antibody is the constant region, 
recombinant techniques can be used to splice and replace the constant region of the 
murine antibody with that of a characteristic human antibody. Current drugs have been 
developed that are more favorably humanized. They are also shown to be more 
effective with less adverse side effects. Further chimerization and other 
improvements in antibody therapy are active fronts of current research. 
This poses a problem: human immune system is able to identify the murine antibody 
as non-self and eliminate the treatment from circulation. This renders the monoclonal 
therapy ineffective.
Immunosuppressive Therapy 
Monoclonal antibodies 
 To suppress the activity of subpopulation of T-cells. 
 To block co-stimulatory signals. 
 Ab to the CD3 molecule of TCR (T cell receptor) complex results in 
a rapid depletion of mature T-cells from the circulation. 
 Ab specific for the high-affinity IL-2 receptor is expressed only on 
activated T-cell, blocks proliferation of T-cells activated in response 
to the alloantigens of the graft. 
 To treat donor’s bone marrow before it is transplanted. 
 Molecules present on particular T-cells subpopulation may also be 
targeted for immunosuppressive therapy. 
 Antibody to CD4 shown to prolong graft survival. 
 Ab specific for implicated cytokine can prolong the survival of graft.
Polyclonal Antibodies 
Antithymocyte globulin-equine (Atgam®) 
Antithymocyte globulin-rabbit (RATG, Thymoglobulin®) 
Polyclonal Antibodies are used in early rejection prophylaxis, treatment 
of rejection. 
Polyclonal antibodies are directed against lymphocyte antigens 
instead of the single-specificity of the monoclonal antibodies, these 
anitlymphocyte antibodies are directed against multiple epitopes. 
Antithymocyte globulin is a polyclonal antibody derived from either 
horses (Atgam®) or rabbits (Thymoglobulin®). The agents contain 
antibodies specific for many common T cell surface antigens including 
CD2, CD3, CD4, CD8, CD11a, CD18. The antithymocyte globulin binds 
lymphocytes that display the surface antigens previously listed. This 
effectively depletes T-cell concentration in the body through 
complement-dependent cytolysis and cell mediated opsonization 
following with T cell clearance from the circulation by the 
reticuloendothelial system (RES). 
Side effects can include 
first-dose effect (cytokine release syndrome) and is related to cytokines 
release by these lymphocytes upon their demise. 
fever, chills, tachycardia, gastrointestinal disturbances,bronchospasm,
Summary 
 CsA, Tac or Sirolimus are the backbone 
of maintenance immunosuppresion 
 Addition of other agents (Steroids, MMF, 
Azathioprine) can be used to decrease 
risk of rejection or allow for lower doses 
of the primary agents. 
 50% of post-OLT deaths are 
directly/indirectly related to 
immunosuppressive medications.
Reading 
 McGuire BM et al. Long-term Management of 
the Liver Transplant Patient: 
Recommendations for the Primary Care Doctor 
American Journal of Transplantation 2009; 9: 
1988–2003 
 Post DJ. Immunosuppression in Liver 
Transplantation. Liver Transplantation, 2005; 11: 
1307-1314

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Rejection cc 2014 jaipur

  • 1. Management of Liver Transplant Rejection Dr Palepu B Gopal MD,FRCA,CCST,FICCM,FCCM Consultant Critical Care Medicine Hyderabad
  • 2. Complications Of Organ Transplantation 1- Rejection 2-Malignancy
  • 3. Causes of Allograft Failure  Primary Nonfunction – slightly more common in Living Donors  Vascular Complications – 10% of patients  Hepatic Artery Thrombosis/Stricture  Portal Vein Thrombosis/Stricture  Hepatic Vein Thrombosis/Stricture  Biliary Complications –  Donors after Cardiac Death  Living Donors  Anastomotic vs nonanastomotic strictures
  • 4. Causes of Allograft Failure- Rejection  Antibody Mediated Rejection – hours to days  10-20% Acute Rejection  Risk 1st 3months>1st year>subsequent years  Chronic Rejection – a primary RF is prior episodes of Acute Rejection.  Acute vs Chronic – ○ time course ○ pattern of liver enzyme abnormalities ○ response to therapy
  • 5. Transplant Rejection – Issues for Critical Care Single organ dysfunction of organ under Rejection MOF related to single organ dysfunction Extended Immunosuppression Infections Drug Interaction Toxicity Sepsis and MOF Drug Toxicity Renal Failure
  • 7. Late Hepatic Allograft Dysfunction : Wiesner et al. Liver Transpl 2001 Rejection Causes reduction or withdrawal of immunosuppressants, erratic absorption poor compliance Poor prognosis Rejection in Hep C Tx High risk for Ac rejection Age less than 30 years Tx for an autoimmune liver disease ALD Child’s A at the time of Tx Interferon for Hep C Low Risk for Ac Rejection Age more than 60 years Tx for Alcoholic liver disease Child’s class C at the time of Tx Immunospp. Regimen high-dose steroids response 80% Others require antilymphocyte therapy Less rejection with tacrolimus than cyclosporine regimens 14% rejection rate with Tacro and sirolimus combination
  • 8. Late Hepatic Allograft Dysfunction Russell H. Wiesner and K.V. Narayanan Menon Liver Transplantation, Vol 7, No 11, Suppl 1 2001
  • 9. Types of Transplant Autograft is self-tissue transferred from one body site to another in the same individual. Isograft is tissue transferred between genetically identical individuals. Allograft is tissue transferred between genetically different members of the same species. Xenograft is tissue transferred between different species
  • 10. Immunology of Transplant Rejection Components of the Immune system involved in graft Rejection : 1) Antigen presenting cells – ○ Dendritic cells ○ Macrophages ○ Activated B Cells 2) B cells and antibodies – ○ Preformed antibodies ○ Natural antibodies ○ Preformed antibodies from prior sensatization ○ Induced antibodies 3) T cells 4) Other cells – ○ Natural killer cells ○ T cells that express NK cell – associated Markers ○ Monocytes/Macrophages
  • 11. 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.
  • 12.  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.
  • 13. 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.
  • 14. Activation of Alloreactive T cells and Rejection of Allografts (SENSATIZATION) Passenger leukocyte Class II MHC. antigen H H T T IL  2 H T H T Donar kidney CTL CTL T DTH DTH T EFFECTOR LYMPH NODE
  • 15. 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.
  • 16. Effector Mechanisms of Allograft Rejection - Types  Hyperacute Rejection  Acute Rejection  Chronic Rejection
  • 17. Hyperacute Rejection  Characterized by thrombotic occlusion of the graft  Begins within minutes or hours after anastamosis  Pre-existing antibodies in the host circulation bind to donor endothelial antigens  Activates Complement Cascade 1.Preformed Ab 2.complement activation 3.neutrophil margination 4.inflammation, 5.Thrombosis
  • 18. Acute Rejection  Vascular and parenchymal injury mediated by T cells and antibodies that usually begin after the first week of transplantation if there is no immunosuppressant therapy  Incidence is high (30%) for the first 90 days  T-cell, macrophage and Ab mediated,  myocyte and endothelial damage,  Inflammation
  • 19. Chronic Rejection  Occurs in most solid organ transplants  Heart  Kidney  Lung  Liver  Characterized by fibrosis and vascular abnormalities with loss of graft function over a prolonged period. Macrophage – T cell mediated Concentric medial hyperplasia Chronic DTH reaction
  • 20. Graft vs. Host Disease  Caused by the reaction of grafted mature T-cells in the marrow inoculum with alloantigens of the host  Acute GVHD  Characterized by epithelial cell death in the skin, GI tract, and liver  Chronic GVHD  Characterized by atrophy and fibrosis of one or more of these same target organs as well as the lungs
  • 21. Clinical Picture and Diagnosis
  • 22. Wyatt (2010) Histopathology 57, 333–341 Biopsy
  • 23. Causes of Liver Test Abnormalities in Asymptomatic Recipient Allograft parenchymal damage Immune-mediated disease rejection and de novo AIH) Recurrent Liver disease Drug toxicity immunosuppressive drugs Alcohol and other toxins De novo infection Bacterial, Viral (de novo HBV and HCV) Space-occupying lesion De novo or recurrent NAFLD Biliary damage Biliary strictures , anastomotic strictures, Hep A Stricture Biliary stones/cast syndrome Recurrent PSC Vascular disease Hepatic artery thrombosis Portal or hepatic vein thrombosis Metabolic disease of Graft Gilbert’s syndrome Nonhepatic disease Hemolysis – indirect bilirubin Bone disease raised ALP Nonhepatic disease Celiac disease Diabetes
  • 24. Late Hepatic Allograft Dysfunction Russell H. Wiesner and K.V. Narayanan Menon Liver Transplantation, Vol 7, No 11, Suppl 1 (November), 2001 Time to first rejection episode among adult liver recipients who rejected following liver transplantation.
  • 26. Episodic Treatment of Rejection Immunotherapy is truly a treatment that delays the inevitability of graft rejection. Rejection Episodes can be treated by the one of the following treatments:  Corticosteroid  Polyclonal and Monoclonal Antibodies  Antiproliferatives Alternative Therapies Xenotransplantation Tissue Engineering Stem Cell Research Induction of Tolerance
  • 27. Recommendations for Prevention and Tt of Rejection  Immunosuppressants recipients should be prescribed and monitored by expertis in that area The choice of agents is multi-factorial, and no one regimen can be recommended for any patient (grade 2, level A) Reviewed at least every 6 months and modified as required Goal of minimizing long term toxicities (grade 1, level B). Rejection can be diagnosed only on the basis of liver biopsy classified according to Banff criteria (grade 1, level A) Long-Term Management of the Successful Adult Liver Transplant: 2012 Practice Guideline by the ASSLD and AST. Michael R. Lucey: LIVER TRANSPLANTATION 19:3-26, 2013
  • 28. Clinical Immunosuppression Two types of immunosuppression are used in transplantation: Induction and Maintenance immunosuppresion Adverse side-effects that include high incidence of opportunistic infection transplant-related malignancies in patients Major goal of immunosuppression Identify the optimal balance of therapy Effective prevention of allograft rejection Minimized Adverse effects, infection & malignancies
  • 29. A cute cellular rejection (ACR) is a very common event that occurs in utpo 70% of orthotopicl iver transplant (OLT) recipients within the first year.l The highest incidence is around 7 to 10 days posttransplantation. ACR occurs i n 10% to 70% of patients, depending on the primary immunosuppression used, the indication for the transplantation, and the definition of rejection. histologic features of portali nfiltrate and endotheliitis, which suggest mild ACR, but without biochemical graft dysfunction, often resolves without adjuvant immunosuppression.3 So, liver biopsies should be delayed until patients develop biochemical graft dysfunction, unexplained fever, or other surrogate markers of rejection. Liver Transplantation, Vol8, No 12 (December), 2002:pp 1147-1 153
  • 31. Timeline for the introduction of immunosuppression medications. Immunosuppression in Liver Transplantation. Post et al. LiverTransplantation, Vol 11, No 11,2005: pp 1307-1314
  • 32. Immunosuppressive Agents Immunosuppression can be achieved in by 1. Surgical ablation 2. Total Lymphoid Irradiation 3. Immunosuppressive drugs
  • 33. Immunosuppressive Drugs Three main immunosuppressant drugs  Cyclosporins act by inhibiting T-cell activation, thus preventing T-cells from attacking the transplanted organ  Azathioprines disrupt the synthesis of DNA and RNA and cell division  Corticosteroids such as prednisolone suppress the inflammation associated with transplant rejection
  • 34. Organ Specific Immunosuppressant Classification  Kidney transplants ○ Basiliximab in combination with cyclosporin and corticosteroids  Kidney transplants ○ Daclizumab in combination with cyclosporin and corticosteroids  Kidney, liver and heart transplants ○ muromonab CD3 (Orthoclone OKT3) along with cyclosporin  Liver transplants Tacrolimus ○ under study for kidney, bone marrow, heart, pancreas, pancreatic island cell, and small bowel transplantation.
  • 35. Induction Therapy Def: prophylactic application of periop antibodies in addition to baseline immunosuppression. (immediate posttransplant) The goal : induce hyporesponsiveness in the organ recipient toward the transplanted organ in order to prevent early post-transplant rejection Only T cells are inhibited and the rest of the patient's immune system would remain fully functional Agents: Earlier nonspecific polyclonal antibodies Today, however, murine monoclonal anti-lymphocyte antibodies, such as OKT3, are often used Antimicrobials are a necessary component
  • 36. Maintenance immunosuppression Drugs administered to maintain immuno-suppression once recipients have recovered from the operative procedure. Agents are either Biological Monoclonal and polyclonal antibodies Generally used in induction protocols Nonbiological agents Mainstay of maintenance protocols. corticosteroids azathioprine cyclosporines
  • 37. Maintenance Therapy Maintenance immunosuppression refers to the classic combination therapy (known clinically as Triple Therapy) to which transplant recipients usually adhere for the rest of their lives. The Combination includes  a corticosteroid  a calcineurine inhibitor  an antiproliferative The Goal Balance between underimmunosuppression and overimmunosuppression Consider potential interactions
  • 38. Calcineurin Inhibitors (CNIs) Calcineurine (cytokines activator ) Inhibitors are used in maintenance immunosuppression. Cyclosporin A From fungus Tolypocladium inflatum selective suppression of CMI via inhibition of T-cell activation standard formulation (Sandimmune) emulsion depends on bile flow, GI motility & food intake Unpredictable bioavailability Microemulsion in lipophilic solvent (Neoral) Predictable bioavailability Drug Interactions Nephrotoxicity – up to 20% post OLT Renal failure Neurological manifestations – 10-28% hyperkalemia, hypomagnesemia, hyperglycemia Hypertension, gingival hyperplasia and hirsutism Immunosuppression in Liver Transplant. Post et al. LiverTransplantation, 2005
  • 40. Tacrolimus From fungus Streptomyces tsukubaensis in Japan Tacrolimus is a microlide antibiotic 100 times more potent than CyA Inhibits calcineurin TAC absorption uninfluenced by presence of bile Lower first year rejection rate better with TAC compared to CyA Hepatitis C infected patients on TAC have longer graft survival Immunosuppression in Liver Transplantation. Post et al. LiverTransplantation, Vol 11, No 11,2005: pp 1307-1314
  • 41. Common Side Effects of Tacrolimus Post-transplant diabetes mellitus Nausea, vomiting, diarrhea Hyperkalemia Tremor Hypertension Hypomagnesemia Headache Renal dysfunction
  • 42. Sirolimus  Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of action ○ blocks response of T and B Cell Activation by cytokines  Theoretical (lab based) antineoplastic and antifungal effects.  Early excitement about renal protective effect- subsequent studies have not confirmed this  Black Box warning – possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting  Recent study of switch from CNI to SRL suggests possible increased mortality  Currently using in those intolerant to CNIs, and in some patients for theoretical antineoplastic and renoprotective actions Hepatology. 2010 Oct;52(4)
  • 43. Sirolimus – Adverse Effects • Anemia • Hypercholesterolemia • Hypertriglyceridemia • Leukopenia • Hyperlipidemia • Interstitial lung disease • Thrombocytopenia • Peripheral edema • Wound dehiscence • Hepatic Artery Thrombosis
  • 45. Corticosteroids Prednisone and Methylprednisolone Corticosteriods Maintenance immunosuppression Teatment of acute rejection Diffuse into cells and bind to specific cytoplasmic receptors progress to the nucleus, inhibit the transcription of the genes of the cytokines Block T cell, APC and Macrophase cytokines IL-1, IL-6, IL-2, INF-γ , and TNF-α Non-specific anti-inflammatory agents acutely reduce lymphocytes & monocytes Pretransplant bolus dose of methylprednisolone 500 to 1,000 mg, followed by rapid taper over next few weeks to minimal dose, i.e., 25-50 mg/day.
  • 46. Common Side Effects of Corticosteroids Hypertension Mental status changes Lipid abnormalities Impaired wound healing Hyperglycemia Cushingoid syndrome Ulcers Myopathy Osteoporosis Fluid retention Cataracts
  • 47. Antiproliferative Agents / Antimetabolites Mycophenolate Mofetil, Azathioprine, Sirolimus Antiproliferative Block the proliferative phase of ACR Maintenance immunosuppression Treatment of rejection Azathioprine Mercaptopurine derivative & antagonises purine metabolism Significant myelosuppression and hepatotoxicity Use decreased dramatically Mycophenolate mofetil and Mycophenolic acid Mycophenolate Mofetil (MMF) Rapidly hydrolyzed in the blood to its active form: MPA MPA inhibits enzyme IMPDH in the pathway of purine biosynthesis Activated lymphocytes are selectively inhibited Nausea, vomiting, diarrhea, Pancytopaenia
  • 48. Antibody Induction  Antithymocyte Globulin – induction/rejection.  Polyclonal antilymphocyte globulin – multiple epitopes on T cell receptor – lead to apoptosis of T-cells  ATGAM (of equine origin)  Thymoglobulin (of rabbit origin)  Monoclonal anti T-Cell antibodies – induction/rejection  Muromonab-CD3 (OKT3) – binds CD3 Antigen on T-Cell receptor – inactivates adjacent T-Cell – leads to rapid drop in T-Cells  IL-2 Receptor Antibodies – induction  Basiliximab (Simulect)  daclizumab (Zenapax).
  • 49. Monoclonal Antibodies Muromonab-CD3 (Orthoclone OKT3®) Used in LTx in 1987 for prophylaxis against acute cellular rejection and later to reduce CNI exposure and treatment of steroid-resistant rejection. OKT3 use today is much lower, with many centers preferring treatment regimens for acute cellular rejection to increasing TAC blood levels and then adding corticosteroid boluses if rejection is still present Daclizumab (Zenapax®) Interleukin-2 Receptor Antagonist (Basiliximab, Simulect®) Monoclonal Antibodies are used in early rejection prophylaxis and treatment of rejection. Monoclonal antibodies are antigen-specific immunosuppressants that will reduce immune response to alloantigens of the graft while preserving the response to alloantigens to unrelated antigens. These agents are specific to blocking T-cell activation, resulting in rapid depletion of T cells from the circulation by binding of antibody coated T cells to Fc receptors on phagocytic cells. The most recently FDA approved monoclonal antibodies are the IL-2 receptor antagonists genetically engineered to possess both human and murine antibody sequences. The chimerization of these antibodies is an attempt to decrease the immunogenicity of the agent. Other monoclonal antibody-based drugs are
  • 50. Monoclonal Antibodies Muromonab-CD3 is the first type of murine monoclonal antibody directed against the ε chain of the CD3 molecule (an integral part of the T Cell Receptor complex) and modulates the receptor and inactivates T-cell function blocking both naïve T cells and CTLs. This results in rapid depletion of T cells from circulation and cytokine release. This antibody is used to treat acute rejection and steroid resistant rejection. Basiliximab is a chimeric (70% human and 30% murine) monoclonal antibody utilized in the prevention of acute organ rejection. This monoclonal antibody has a specificity and high affinity for the α subunit of the interleukin (IL)-2 receptor (IL-2Rα, also known as CD25 or Tac) preventing IL-2 from binding to the receptor on the surface of activated T cells. By acting as an IL-2Ra antagonist, Basiliximab inhibits IL-2-mediated activation and proliferation of T cells, the critical step in the cascade of cellular immune response of allograft rejection. Therefore, Basiliximab has a long half-life of approximately 7-12 days and saturates the IL-2 receptor for up to 59 days. Due to its high percentage of humanization in its antibody sequences the occurrence and acuteness of adverse effects is significantly lower when used with standard immunotherapy.
  • 51. Monoclonal Antibodies Muromonab – CD3 Daclizumab is a similar agent to Basiliximab, but is a more humanized IgG monoclonal antibody (90% human and 10% murine). It also binds to and inhibits the α-subunit of IL-2 receptor and thus works in a manner similar to Basiliximab. Daclizumab is able to saturate the IL-2 receptor twice as long as Basiliximab. Because it is more humanized, there are less side effects associated with Daclizumab. Side Effects – HAMA One of the major problems affecting monoclonal therapy is the side effects associated with the HAMA (Human anti-Murine Antibody) response and serum sickness. These are both directly caused by the structure of the antibodies. Laboratories routinely use murine antibodies as a starting point for monoclonal antibodies. A counteractive measure includes humanizing (or chimerizing) the antibody. Because the only immunologically offensive portion of the antibody is the constant region, recombinant techniques can be used to splice and replace the constant region of the murine antibody with that of a characteristic human antibody. Current drugs have been developed that are more favorably humanized. They are also shown to be more effective with less adverse side effects. Further chimerization and other improvements in antibody therapy are active fronts of current research. This poses a problem: human immune system is able to identify the murine antibody as non-self and eliminate the treatment from circulation. This renders the monoclonal therapy ineffective.
  • 52. Immunosuppressive Therapy Monoclonal antibodies  To suppress the activity of subpopulation of T-cells.  To block co-stimulatory signals.  Ab to the CD3 molecule of TCR (T cell receptor) complex results in a rapid depletion of mature T-cells from the circulation.  Ab specific for the high-affinity IL-2 receptor is expressed only on activated T-cell, blocks proliferation of T-cells activated in response to the alloantigens of the graft.  To treat donor’s bone marrow before it is transplanted.  Molecules present on particular T-cells subpopulation may also be targeted for immunosuppressive therapy.  Antibody to CD4 shown to prolong graft survival.  Ab specific for implicated cytokine can prolong the survival of graft.
  • 53. Polyclonal Antibodies Antithymocyte globulin-equine (Atgam®) Antithymocyte globulin-rabbit (RATG, Thymoglobulin®) Polyclonal Antibodies are used in early rejection prophylaxis, treatment of rejection. Polyclonal antibodies are directed against lymphocyte antigens instead of the single-specificity of the monoclonal antibodies, these anitlymphocyte antibodies are directed against multiple epitopes. Antithymocyte globulin is a polyclonal antibody derived from either horses (Atgam®) or rabbits (Thymoglobulin®). The agents contain antibodies specific for many common T cell surface antigens including CD2, CD3, CD4, CD8, CD11a, CD18. The antithymocyte globulin binds lymphocytes that display the surface antigens previously listed. This effectively depletes T-cell concentration in the body through complement-dependent cytolysis and cell mediated opsonization following with T cell clearance from the circulation by the reticuloendothelial system (RES). Side effects can include first-dose effect (cytokine release syndrome) and is related to cytokines release by these lymphocytes upon their demise. fever, chills, tachycardia, gastrointestinal disturbances,bronchospasm,
  • 54. Summary  CsA, Tac or Sirolimus are the backbone of maintenance immunosuppresion  Addition of other agents (Steroids, MMF, Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents.  50% of post-OLT deaths are directly/indirectly related to immunosuppressive medications.
  • 55. Reading  McGuire BM et al. Long-term Management of the Liver Transplant Patient: Recommendations for the Primary Care Doctor American Journal of Transplantation 2009; 9: 1988–2003  Post DJ. Immunosuppression in Liver Transplantation. Liver Transplantation, 2005; 11: 1307-1314