Anshul trans rejection

76
TRANSPLANT REJECTION Dr. Anshul

Transcript of Anshul trans rejection

Page 1: Anshul trans rejection

TRANSPLANT REJECTION

Dr. Anshul

Page 2: Anshul trans rejection

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.

Page 3: Anshul trans rejection

Transplantation

• The process of transferring cells, tissues or organs called a graft, from one individual and placing them into a (usually) different individual.

Page 4: Anshul trans rejection

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

Page 5: Anshul trans rejection

Nobel Laureates

Joseph Murray E D Thomas

Sir Peter Medawar – second set rejection First kidney transplant in identical twins

19901960

Page 6: Anshul trans rejection

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

Page 7: Anshul trans rejection

Based on genetic relationship

Page 8: Anshul trans rejection

Organ transplants

• Kidney• Liver • Heart• Bone marrow• Skin• Cornea

• Pancreas• Bone• Vascular tissue• Neural tissue• Cartilage

Page 9: Anshul trans rejection

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

Page 10: Anshul trans rejection

Cells of Immune system –

TCR complex & other molecules involved in T- cell activation

T cell

Page 11: Anshul trans rejection

Cells of Immune system – B cell

Page 12: Anshul trans rejection

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.

Page 13: Anshul trans rejection

Major Histocompatibility molecules(HLA Complex)

Page 14: Anshul trans rejection

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

Page 15: Anshul trans rejection

Antigen processing and display by MHC Molecule

Page 16: Anshul trans rejection

HLA ALLELES

Page 17: Anshul trans rejection

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

Page 18: Anshul trans rejection
Page 19: Anshul trans rejection

Rejection mainly involves• First set rejection• Second set rejection

Page 20: Anshul trans rejection

Allograft rejection

Page 21: Anshul trans rejection

Experimental demonstration - T cells transfer allograft rejection

Page 22: Anshul trans rejection

Mechanism of Rejection

• Sensitization stage- - direct pathway - indirect pathway • Effector stage

Page 23: Anshul trans rejection

DIRECT PATHWAY

T Cell recognizes unprocessed allogenic MHC molecule on graft APCs. (Passenger Leukocyte Hypothesis)

Page 24: Anshul trans rejection

INDIRECT PATHWAY

Page 25: Anshul trans rejection

EFFECTOR PHASE

Page 26: Anshul trans rejection

TYPES OF GRAFT REJECTION

• Hyperacute rejection

• Acute rejection

• Chronic rejection

Page 27: Anshul trans rejection

Hyperacute Rejection

• Occurs within minutes of transplantation• Pre-existing IgM antibodies against– ABO blood group antigens– Class I MHC molecules .

Page 28: Anshul trans rejection

Steps in hyperacute rejection

Page 29: Anshul trans 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

Page 30: Anshul trans rejection

Chronic Rejection

• Occurs over months to years

• Accelerated arteriosclerosis

• Fibrosis with loss of normal organ structures

Page 31: Anshul trans rejection

Non rejection complications

• Transport injury• Drug toxicity• Infection• Malignancy• Recurrence of disease

Page 32: Anshul trans rejection

Role of pathologist and biopsy

• Initial patient evaluation – failing organ• Blood matching and histocompatibility,

assessing of donor organ• Monitoring rejection- Protocol biopsies

Page 33: Anshul trans rejection

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.

Page 34: Anshul trans rejection

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

Page 35: Anshul trans rejection

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)

Page 36: Anshul trans rejection

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.

Page 37: Anshul trans rejection

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

Page 38: Anshul trans rejection

Banff classification for rejection

Page 39: Anshul trans rejection

Non rejection complications:

• Cyclosporin A nephrotoxicity

• Recurrent renal disease

• De novo glomerulonephritis

• Infection.

Page 40: Anshul trans rejection

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.

Page 41: Anshul trans rejection

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.

Page 42: Anshul trans rejection

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.

Page 43: Anshul trans rejection

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-

Page 44: Anshul trans rejection

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

Page 45: Anshul trans 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

Page 46: Anshul trans rejection

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

Page 47: Anshul trans rejection

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 .

Page 48: Anshul trans rejection

HEART TRANSPLANTATION

Acute humoral rejection:• High death rate.HPE-• Cellular infiltrate absent in endomyocardium.• Endothelial swelling and edema• Immunofluorescence - Immunoglobulins on

endothelial surface (Diagnostic).

Page 49: Anshul trans rejection

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

Page 50: Anshul trans rejection

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.

Page 51: Anshul trans rejection

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

Page 52: Anshul trans rejection

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

Page 53: Anshul trans rejection

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

Page 54: Anshul trans rejection

Perivascular infiltrate extending to adjacent interstitium.

Acute lung rejection:

Page 55: Anshul trans 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)

Page 56: Anshul trans rejection

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

Page 57: Anshul trans rejection

LUNG TRANSPLANTATION

Chronic rejection

Occlusion of small airways by fibrosis (Bronchiolitis obliterans)

Page 58: Anshul trans rejection

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

Page 59: Anshul trans rejection

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

Page 60: Anshul trans rejection

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.

Page 61: Anshul trans rejection

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

Page 62: Anshul trans rejection

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

Page 63: Anshul trans rejection

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.

Page 64: Anshul trans rejection

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.

Page 65: Anshul trans rejection

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)

Page 66: Anshul trans rejection

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

Page 67: Anshul trans rejection

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.

Page 68: Anshul trans rejection

PREVENTION OF GRAFT REJECTION

Histocompatibility testing

Post-operative immunosuppressive therapy

Page 69: Anshul trans rejection

Histocompatibility testing

• ABO typing• HLA typing: determination of HLA phenotype

of donor & recipient

Page 70: Anshul trans rejection

• 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

70

Page 71: Anshul trans rejection

Post-operative immunosuppressive therapy

• Anti-inflammatory drugs (glucocorticosteroids)

• Cytotoxic drugs• Azathioprine• Cyclophosphamide• Mycophenolate mofetil

- Calcineurin inhibitors- Cyclosporine A- Tacrolimus- Rapamycin

Page 72: Anshul trans rejection

• Biological response modifiers - anti thymocyte globulin - anti T-cell monoclonal antibodies

Page 73: Anshul trans rejection

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).

Page 74: Anshul trans rejection

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.

Page 75: Anshul trans rejection

THANK YOU

Page 76: Anshul trans rejection