rejection cc 2014 jaipur
DESCRIPTION
Critical care aspects of transplant rejectionTRANSCRIPT
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/StricturePortal Vein Thrombosis/StrictureHepatic Vein Thrombosis/Stricture
Biliary Complications – Donors after Cardiac DeathLiving 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 andEtiopathogenesis
of Rejection
Rejection
Causes reduction or withdrawal of immunosuppressants, erratic absorptionpoor compliance
Poor prognosis Rejection in Hep C TxHigh risk for Ac rejection Age less than 30 years Tx for an autoimmune liver disease
ALDChild’s A at the time of TxInterferon for Hep C
Low Risk for Ac Rejection Age more than 60 yearsTx for Alcoholic liver diseaseChild’s class C at the time of Tx
Immunospp. Regimen high-dose steroids response 80%Others require antilymphocyte therapyLess rejection with tacrolimus than
cyclosporine regimens14% rejection rate with Tacro and
sirolimus combination
Late Hepatic Allograft Dysfunction : Wiesner et al. Liver Transpl 2001
Late Hepatic Allograft DysfunctionRussell H. Wiesner and K.V. Narayanan MenonLiver 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 MHCantigen
2IL HT HT
HTHT
Donar kidney
CTLDTHTCTL
DTHT
LYMPH NODEEFFECTOR
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 Ab2.complement activation3.neutrophil margination4.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
HeartKidneyLungLiver
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 GVHDCharacterized 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 damageImmune-mediated disease
rejection and de novo AIH)Recurrent Liver disease Drug toxicity
immunosuppressive drugsAlcohol and other toxinsDe novo infection
Bacterial, Viral (de novo HBV andHCV)
Space-occupying lesion De novo or recurrent NAFLD
Biliary damageBiliary strictures , anastomotic strictures, Hep A StrictureBiliary stones/cast syndromeRecurrent PSC
Vascular diseaseHepatic artery thrombosisPortal or hepatic vein thrombosis
Metabolic disease of GraftGilbert’s syndrome
Nonhepatic diseaseHemolysis – indirect bilirubinBone disease raised ALP
Nonhepatic diseaseCeliac diseaseDiabetes
Time to first rejection episode among adult liverrecipients who rejected following liver transplantation.
Late Hepatic Allograft DysfunctionRussell H. Wiesner and K.V. Narayanan MenonLiver Transplantation, Vol 7, No 11, Suppl 1 (November), 2001
Prevention and
Management 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
Episodic Treatment of Rejection
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 includehigh 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 commonevent that occurs in utpo 70% of orthotopicl ivertransplant (OLT) recipients within the first year.l Thehighest 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 definitionof rejection.histologic features of portali nfiltrate and endotheliitis, which suggest mildACR, but without biochemical graft dysfunction, oftenresolves without adjuvant immunosuppression.3So, liver biopsies should be delayed until patientsdevelop biochemical graft dysfunction, unexplainedfever, 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 TherapyDef: 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 rejectionOnly T cells are inhibited and the rest of the patient's immune system would remain fully functional
Agents: Earlier nonspecific polyclonal antibodiesToday, however, murine monoclonal anti-lymphocyte antibodies, such as OKT3, are often usedAntimicrobials 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.
corticosteroidsazathioprine cyclosporines
Maintenance TherapyMaintenance 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 bioavailabilityMicroemulsion in lipophilic solvent (Neoral)
Predictable bioavailabilityDrug InteractionsNephrotoxicity – up to 20% post OLT Renal
failureNeurological manifestations – 10-28%hyperkalemia, hypomagnesemia,
hyperglycemiaHypertension, gingival hyperplasia and
hirsutism
Immunosuppression in Liver Transplant. Post et al. LiverTransplantation, 2005
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 survivalImmunosuppression in Liver Transplantation. Post et al. LiverTransplantation, Vol 11, No 11,2005: pp 1307-1314
Post-transplant diabetes mellitus
Nausea, vomiting, diarrhea
Hyperkalemia
Tremor
Hypertension
Hypomagnesemia
Headache
Renal dysfunction
Common Side Effects of Tacrolimus
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
CorticosteroidsPrednisone 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 CorticosteroidsHypertension
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 inhibitedNausea, 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/rejectionMuromonab-CD3 (OKT3) – binds CD3 Antigen
on T-Cell receptor – inactivates adjacent T-Cell – leads to rapid drop in T-Cells
IL-2 Receptor Antibodies – inductionBasiliximab (Simulect) daclizumab (Zenapax).
Monoclonal AntibodiesMuromonab-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 regimensfor 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 still in clinical trials for FDA approval.
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 AntibodiesAntithymocyte 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 antigensinstead 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 includefirst-dose effect (cytokine release syndrome) and is related to cytokines release by these lymphocytes upon their demise. fever, chills, tachycardia, gastrointestinal disturbances,bronchospasm, and fluctuations of blood pressure,which all can be ameliorated by pretreatment with corticosteroids, diphenhydramine, and acetaminophen.20
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