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TRANSPLANT REJECTION
Dr. Anshul
TRANSPLANT REJECTION
• Introduction• History• Classification of graft• Indication for transplantation• Rejection and Mechanism.• Types of graft rejection• Rejection of organs – Clinical features, HPE.• Prevention of rejection.
Transplantation
• The process of transferring cells, tissues or organs called a graft, from one individual and placing them into a (usually) different individual.
History
• 1908 – Alexis Carrel – first systemic study of transplantation
• 1932 – Padgett – longer survival of allografts in family members than in unrelated individuals
• 1954 – E. D. Thomas and J. Murray – first kidney transplant in identical twins
• 1962 – Murray – successful grafting of unrelated cadaveric kidney
Nobel Laureates
Joseph Murray E D Thomas
Sir Peter Medawar – second set rejection First kidney transplant in identical twins
19901960
Classification of grafts
• Anatomical site of origin- - orthotopic - heterotopic• Genetic relation between donor and recipient- - autograft - isograft - allograft - xenograft• Living or non-living• Fresh or stored
Based on genetic relationship
Organ transplants
• Kidney• Liver • Heart• Bone marrow• Skin• Cornea
• Pancreas• Bone• Vascular tissue• Neural tissue• Cartilage
Need for transplantation
Bone marrow-Sickle cell anaemia-Thalassemia-Lymphomas-Leukemias
Liver-Wilsons’ disease-Tyrosinemia-Extra hepatic biliary atresia
Kidney- End stage renal disease
Lung
-Restrictive lung diseases-Pulmonary vascular disease
Cells of Immune system –
TCR complex & other molecules involved in T- cell activation
T cell
Cells of Immune system – B cell
Major Histocompatibility Complex (MHC)
• Set of cell surface molecule encoded by a large gene family, control a major part of immune system.
• Major function of MHC- bind to peptide fragments derived from foreign antigen and display them on cell surface for recognition by appropriate T cell.
• MHC determines the compatibility between donor and recipient for organ transplantation.
• In humans MHC region- 6th Chromosome.
Major Histocompatibility molecules(HLA Complex)
Characteristics of MHC• Most polymorphic genes present in the genome• Genes are expressed codominantly• Responsible for strong rejection• MHC class I molecules - almost all nucleated cells• MHC class II molecules – APCs, B cells,
Macrophages
Antigen processing and display by MHC Molecule
HLA ALLELES
Rejection Immunological phenomenon associated with
inflammatory reaction leading to the failure of graft.
Allograft rejection• Alloantigens - major antigens - MHC - minor antigens• Alloreactive cells - lymphocytes - antibodies
Rejection mainly involves• First set rejection• Second set rejection
Allograft rejection
Experimental demonstration - T cells transfer allograft rejection
Mechanism of Rejection
• Sensitization stage- - direct pathway - indirect pathway • Effector stage
DIRECT PATHWAY
T Cell recognizes unprocessed allogenic MHC molecule on graft APCs. (Passenger Leukocyte Hypothesis)
INDIRECT PATHWAY
EFFECTOR PHASE
TYPES OF GRAFT REJECTION
• Hyperacute rejection
• Acute rejection
• Chronic rejection
Hyperacute Rejection
• Occurs within minutes of transplantation• Pre-existing IgM antibodies against– ABO blood group antigens– Class I MHC molecules .
Steps in hyperacute rejection
Acute Rejection• Occurs within days or weeks after transplantation.
• Mediated by IgG antibodies
1- Acute cellular rejection – T cell mediated• Activated CD4+ T cells -> Cytokines secretion -> Inflammation in
graft.• Increased vascular permeability, local accumulation of mononuclear
cells and graft injury by the activated macrophages.
2- Acute antibody-mediated rejection• Mediated by antidonor antibodies produced after transplantation.• Microvascular endothelitis, interstitial inflammation, parenchymal
cell damage
Chronic Rejection
• Occurs over months to years
• Accelerated arteriosclerosis
• Fibrosis with loss of normal organ structures
Non rejection complications
• Transport injury• Drug toxicity• Infection• Malignancy• Recurrence of disease
Role of pathologist and biopsy
• Initial patient evaluation – failing organ• Blood matching and histocompatibility,
assessing of donor organ• Monitoring rejection- Protocol biopsies
Kidney • Most common solid organ• End stage renal disease- DM• Evaluation : FNAC/ Urine analysis/ Biopsy.
Hyper acute rejection - Fibrin and antibodies, PMN’s, Haemorrhage, Cortical
necrosis.
Hyperacute rejection of kidney allograft-platelet and fibrin thrombi, neutrophil infiltration, severe ischemic injury in a glomerulus.
Acute rejection: Rapid decline in urine output, rise in Serum Creatinine,
Tenderness and edema of graftAcute antibody-mediated (humoral) rejection-
inflammation in peritubular capillaries(capillaritis)
Immunoperoxidase stain- C4d deposition in peritubular capillaries and a glomerulus
Acute T cell–mediated (cellular) rejection:
Tubulointerstitial pattern (Common)Inflammatory cells in the interstitium and between epithelial cells of the tubules (tubulitis)
Vascular pattern- Rejection vasculitis, with inflammatory cells attacking and undermining the endothelium (endotheliitis)
Chronic rejection:
Gradual and progressive decline of renal function in absence of specific cause that develops over months to years after transplantation.• Pathogenesis unclearChronic rejection is dominated by vascular changes –1. Intimal thickening with inflammation.2. Glomerulopathy with duplication of the basement membrane.3. Peritubular capillaritis with multilayering of peritubular capillary
basement membranes.• Interstitial fibrosis and tubular atrophy with loss of renal
parenchyma -secondary to the vascular lesions. • Interstitial mononuclear cell infiltrates, including NK
cells and plasma cells.
Chronic rejection:
Glomerulus-inflammatory cells within the capillary loops (glomeruliitis), accumulation of mesangial matrix, and duplication of the capillary basementmembrane.
Interstitial fibrosis and tubular atrophy. (trichrome stain), contrasted with the normal kidney. Artery-prominent arteriosclerosis
Banff classification for rejection
Non rejection complications:
• Cyclosporin A nephrotoxicity
• Recurrent renal disease
• De novo glomerulonephritis
• Infection.
Liver transplantation
Hyperacute rejection: • Uncommon – size & functional reserve and sinusoidal architecture limits ischemia in focal thrombosis.• Occurs- preexisting antibodies.• HPE - Arteritis, neutrophilic infiltrate with zonal or diffuse necrosis.
Acute rejection: Reversible form of cell mediated
rejection.Clinical features – fever, change in
mental status, decreased bile output and abnormal hepatic enzymes
Diagnostic triad: portal inflammatory lymphoid
infiltrate, bile duct damage, endothelitis.
Lymphocytes, eosinophils, occasionally PMNs but no Plasma cells
Liver transplantation
Transplanted liver with acute cellular rejection. Mixed inflammatory cell infiltration in portal tracts, bile duct damage, and endotheliitis.
Liver rejection grading-University of Minnesota grading system:
Diagnosis Histologic features
Non diagnostic of rejection
Lymphocyte or mixed portal infiltrate, <50% damaged bile ducts, no endothelitis
Acute rejection grade 1 As above with endothelitis
Acute rejection grade 2 Lymphocyte or mixed portal infiltrate, >50% damaged bile ducts, with/without endothelitis
Acute rejection grade 3 Acute rejection plus arteritis, paucity of bile ducts, or central hepatocellular ballooning with confluent dropout of hepatocytes.
Chronic rejection: - Irreversible - 6 -20%. Cases.Synonyms- Ductopenic rejection & Vanishing bile duct syndromeTwo histological pattern-
1-Chronic vascular rejection – obliterated endarteritis – ischemic damage – liver failure Risk factors – prior rejection, CMV, MHC matching at class I with
mismatch of class II- Gradual liver failure – increased biliary enzymes and bilirubin
and decrease proteins- Biopsy – central ischemic changes associated with loss of
interlobular bile ducts.
Liver transplantation-
2-Pure Vanishing bile duct syndrome/ progressive rejection with paucity of ducts:
• Near total loss of ducts without ischemic changes.• C/F- Elevated bilirubin, minimal elevation of enzymes
and no effect on protein synthesis.• Reversible even though chronic
CHRONIC REJECTION
Liver transplantation-Non rejection complications:• Reperfusion injury• Infections- Hep B,C• Drugs-Cyclosporin A• Recurrence- HCC.
Reperfusion injury in liver allograft- severe cholestasis and balloning affecting perivenular & mid zonal hepatocytes
Time period Common diagnosis Less likely diagnosis
First week Vascular anastomosesAcute rejectionPrimary graft failure
Hyperacute reactionDrug reactionOpportunistic infection
1week to 2 months
Acute rejectionOpportunistic infectionDrug reactionBiliary anastomoses
Chronic vascular rejectionVanishing bile duct syndrome
2 months and beyond
Chronic vascular rejectionVanishing bile duct syndromeRecurrence of original diseaseHepatitis B or C
Acute rejectionDrug reactionOpportunistic infectionTechnical problems
Differential diagnosis of liver dysfunction post transplantation
HEART TRANSPLANTATION• Less complicated• Protocol biopsies
Acute rejection• Cell mediated(Common). Reversible• Subtle cardiac enlargement, ECG changes, decreased ejection
fraction to cardiac failure• Interstitial infiltrate of lymphocytes, with/without myocyte
damage or necrosis .
HEART TRANSPLANTATION
Acute humoral rejection:• High death rate.HPE-• Cellular infiltrate absent in endomyocardium.• Endothelial swelling and edema• Immunofluorescence - Immunoglobulins on
endothelial surface (Diagnostic).
Acute cardiac rejection grading systemGrade Description
0 No rejection
1A Focal(perivascular/interstitial) infiltrate without necrosis
1B Diffuse but sparse infiltrate without necrosis
2 One focus with aggressive infiltration or focal myocyte damage or both
3A Multifocal aggressive infiltration or focal myocyte damage or both
3B Diffuse inflammatory process with necrosis
4 Diffuse aggressive polymorphous infiltrate with myocyte necrosis, edema or haemorrhage or all signs
HEART TRANSPLANTATION
Chronic rejection: Insidious process• Concentric narrowing of coronary arteries. • Intima – foamy histiocytes, smooth muscle cells, fibroblasts• Arteriopathy- Concentric, continuous, rapid development &
involve small branches – r/o atherosclerosis• Asymptomatic until sudden death due to ischemia.
Technical problems: Related to biopsy interpretation• Same biopsy site – Ventricular septum near apex of right
ventricle – fibrosis and lymphocytic infiltration.• Perioperative ischemic events – small areas of necrosis,
granulation change.• Quilty effect – dense subendocardial accumulation of
small lymphocytes with interspersed thickened blood vessels – Cyclosporin A
LUNG TRANSPLANTATIONHyperacute rejection: within 48 hours. Previous sensitization• Gross- Congestion and edema, copious frothy blood stained fluid.• Biopsy – congestion, edema, haemorrhage, thrombosis, neutrophils, alveolar damage.Immunofluorescence – IgG in vessel wall
Neutrophils engorge the blood vessels and enters in to alveolar interstitium and lumen
LUNG TRANSPLANTATION
Acute rejection:40-75% casesC/F- Fever, dyspnea, cough.X-Ray- lung infiltrate/pleuropulmonary opacificationHPE- Prerequisite for biopsy (presence of vessels)Perivascular infiltrate extending to adjacent interstitium.Endothelitis and peribronchial inflammation
Perivascular infiltrate extending to adjacent interstitium.
Acute lung rejection:
Acute pulmonary rejection grading system
• Grade 0 – no significant abnormality• Grade 1 – minimal (difficult to find perivenular
mononuclear infiltrate)• Grade 2 – Mild (easily found perivenular,
predominantly mononuclear infiltrate)• Grade 3 – moderate (easily found perivenular
infiltrate with interstitial infiltrate)• Grade 4- Severe (as grade 3 with alveolar injury, fibrin
exudates, membranes)
Chronic rejection: • Incidence- 25 – 70%• Progressive shortness of breath.• HPE-• Bronchiolitis obliterans- Partial or complete occlusion
of small airways by fibrosis, with or without active inflammation
• Patchy, difficult to diagnose via transbronchial biopsy. • Long-standing-Bronchiectasis, pulmonary fibrosis.
LUNG TRANSPLANTATION
LUNG TRANSPLANTATION
Chronic rejection
Occlusion of small airways by fibrosis (Bronchiolitis obliterans)
LUNG TRANSPLANTATION
Technical problems – Reimplantation response – Decreased pulmonary function with impaired ventilation, decreased compliance and edema. (reperfusion injury) Biopsy – dilated lymphatics, edema neutrophilic infiltration
Infections – P. carinii pneumonia, CMV, HSV, EBV, Fungi.
Recurrence of disease
PANCREAS TRANSPLANTATION • Diabetes mellitus
Offers effective therapy- Achieving Insulin independence, superior metabolic control, preventing complications.
• With kidney (usually)• Whole or segmental pancreas with duodenal segment draining
into bladder or enteric drainage Advantages – lower risk of thrombosis, pancreatitis, fistula, direct
access to secretions and monitoring of graft by urine tests.Disadvantages – hematuria, urine leaks, cystitis, urethral stricture,
infection, stone formation, metabolic problems, reflux pancreatitis
Acute rejection:• Renal rejection precedes• Fever, leukocytosis, pain and tender abdomen (mimic
pancreatitis)
Diagnosis of pancreas allograft rejection:Serologic parameters:Endocrine – Glucose, insulin, c peptide, glucagon.Exocrine – Trypsin, pancreatic specific protein, amylase.
Immune – IL2 receptor, microglobulin, c reactive protein.
Proposed classification - Pancreatic rejectionDiagnosis Features seen
No rejection Normal architecture, no inflammation
Consistent with acute rejection
Patchy mononuclear or polymorphous infiltration with or without acinar and vascular destruction.
Mild acute rejection Patchy mononuclear or polymorphous infiltration with possible acinar and vascular destruction
Severe acute rejection Patchy mononuclear or polymorphous infiltration acinar and vascular destruction with or without fibrinoid necrosis
Chronic rejection Dense mononuclear infiltrate, fibrosis, thrombosis
HEMATOPOETIC STEM CELL TRANSPLANTATION (HSC)
Hematologic malignancies.Bone marrow failure syndromes- aplastic anemia.Inherited defects (sickle cell anemia, Thalassemia)Problem unique to HSC Transplantation Graft versus-host disease (GVHD) Immunologically competent cells /precursors are transplanted
into immunologically crippled recipients and transferred cells recognize alloantigens in the host & attack host tissues.
Types- - Acute GVHD - Chronic GVHD
Acute GVHD -
• Within 100 days of transplantation• Immune system involvement and Epithelial
cell necrosis• C/F- skin rash, jaundice and diarrhea.
Skin – basal cell destruction, lymphocytic infiltrateLiver – Congestion, hemorrhage, destruction ofsmall bile ductsGastrointestinal tract – focal crypt lesion, death of basal cells.
Chronic GVHD• More than 100 days (80-400days).• Graft CD4 Helper T cell react with host B cell.
• Skin- Extensive cutaneous injury, destruction of skin appendages, fibrosis of dermis- resemble systemic sclerosis
• Liver- cholestatic jaundice.
• Gastrointestinal tract – Esophageal strictures.
Skin graft • Burn therapy• Ability to grow- Epidermal cell culture(Provides new
opportunity)
• 2 TypesFull thickness (Dermis and epidermis) Split thickness-(Epidermis and papillary dermis).• Rejection - MHC incompatibility.• Primary target – Endothelial cells of dermal vessels
(CD4cells).• secondary target– Epidermal cells. (CD8 cells)
CORNEAL TRANSPLANTATION Most successful living tissue transplantation.
• Immunologically privileged site – Largely avascular• Graft- Full thickness, partial thickness.• Signs – local hyperemia, small keratin precipitates,
vasodilation, edema, vascularization and eventually opacification.
• HPE: lymphoid hyperplasia at limbus, vascularization
INTESTINAL TRANSPLANT
• Celiac disease, short bowel syndrome.• Clinical infancy stage- Difficult double barrier1-Rejection 2-GVHD severe, large cargo of highly activated lymphoid tissue transplant in to host.
PREVENTION OF GRAFT REJECTION
Histocompatibility testing
Post-operative immunosuppressive therapy
Histocompatibility testing
• ABO typing• HLA typing: determination of HLA phenotype
of donor & recipient
• Typing methods-1. Tissue typing-
- Microlymphocytotoxicity test - Mixed lymphocyte reaction
2. Cross matching 3. Molecular methods-
- PCR - SBT - SSP - SSOP4. Detection of preformed antibodies - ELISA - Flow cytometry
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Post-operative immunosuppressive therapy
• Anti-inflammatory drugs (glucocorticosteroids)
• Cytotoxic drugs• Azathioprine• Cyclophosphamide• Mycophenolate mofetil
- Calcineurin inhibitors- Cyclosporine A- Tacrolimus- Rapamycin
• Biological response modifiers - anti thymocyte globulin - anti T-cell monoclonal antibodies
SUMMARY
• Role of pathologist-• Biopsy of failing organ.• Matching of blood types and histocompatibility
of graft.• Verify viability of tissue while transplantation.• Histopathological evaluation- Monitoring
rejection, complication (Infection, drug toxicity, disease recurrence).
REFERENCES• Ivan Damjonav, James Linden, Anderson’s Pathology,Tenth edition.Volume I. New Delhi:
Elsevier;2009. pg 548-591• Kumar V, Abbas A K, Fausto N, Aster J C, Robbins and Cotrans Pathological basis of disease,
8th edition.USA:Elsevier;2010. p233-237.• Ivan Riott, Jonathan Brostoff, David Male, Immunology.6th edition.Spain: Mosby
international limited;2001. pg pg 385-394• Arthur Rabson, Ivan.M.Riott,Peter J Delves, Really Essential Medical Immunology.2nd
edition.New Delhi:Blackwell Publishing Limited;2005. pg 164-170• Tristram.G.Parslow,Daniel P stites,Abba I Terr, John B Imboden, Medical Immunology. 10th
edition.Singapore :Mc Graw Hill;2001.pg 82-90• Peter J Delves, Seamus J Martin , Dennes R Burton,Ivan.M.Riott, Roitt’s Essentialal
Immunology.12th edition.: Singapore : Wiley - Blackwell Publishing Limited;2011. pg 423-440.
• K. Solez, R. B. Colvin, L. C. Racusen et al., “Banff 07 classification of renal allograft pathology: updates and future directions,” American Journal of Transplantation, vol. 8, no. 4, pp. 753–760, 2008.
• R. B. Colvin and R. N. Smith, “Antibody-mediated organallograft rejection,” Nature Reviews Immunology, vol. 5, no. 10, pp. 807–817, 2005.
• H. E. Feucht, “Complement C4d in graft capillaries - The missing link in the recognition of humoral alloreactivity,” American Journal of Transplantation, vol. 3, no. 6, pp. 646–652, 2003.
THANK YOU