Transplant Rejection

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Transplant Rejection
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Transplant rejection

• Recipient immune system identify the graft/
  transplanted organ as foreign
• Antigens responsible for Transplant rejection is
  HLA molecule
• Any two individuals express 2 different HLA
  protein
• Transplant rejection involves different types of
  Hypersensitivity reaction

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Transplant rejection

• Autograft Donor recipient is same individual
• Isograft - Donor recipient is same genotype
• Allograft - Donor recipient is of same species
  but different genotype
• Xenograft Donor is different species from that
  of recipient
• Skin, kidney, BM, heart, lung, liver, cornea

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Transplant rejection

• Rejection is a complex process in which both cell
  mediated immunity circulating Ab play a role
• T cell mediated reaction
• Antibody mediated reaction

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Transplant rejection

• T cell mediated reaction
• CD4 helper cells mediate delayed
  hypersensitivity reaction
• CD8 CTLS mediate graft cell destruction

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Transplant rejection

• Antibody mediated reaction
• Exposure to class I class II HLA antigen evokes
  antibody production
• Tissue damage Initial target is graft
  vasculature
• Complement dependent cytotoxicity
• ADCC
• Immune complex mediated

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Transplant rejection

• Morphology underlying mechanism
• Hyperacute rejection
• Acute rejection
• Chronic rejection

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Hyper acute rejection

• Within minutes/ hours after transplantation
• Kidney cyanotic, flaccid excrete few drops of
  blood
• Occurs in sensitized recipient preformed Ab in
  circulation
• Ag-Ab complex deposited on vessel wall
  activation of complement (Arthus reaction)

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Hyper acute rejection

• Microscopy
• Neutrophils in arterioles, glomeruli
  peritubular capillaries
• Fibrin platelet thrombi
• Vascular endothelial damage
• Fibrinoid necrosis of arterial wall - Infarction

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Acute rejection

• Within few days in untreated patients
• Sudden onset months/ years later, after
  immunosuppression is terminated
• cell mediated (Acute cellular rejection)
• Ab mediated injury (Acute rejection vasculitis)

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Acute cellular rejection

• ? Creatinine level followed by renal failure
• Extensive interstitial mononuclear cell
  infiltration, edema hemorrhage
• Focal tubular necrosis
• Endothelitis
• In the absence of arteritis- patients responds to
  immunosuppressive therapy

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Acute rejection vasculitis

• Mediated by Anti-donor antibody
• Necrotizing vasculitis
• Marked thickening of intima by proliferating
  fibroblasts, myocyte foamy macrophages
• infarction
• renal cortical atrophy

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Chronic rejection

• Progressive raise in creatinine over 4-6 months
• Vascular changes dense intimal fibrosis
• Interstitial fibrosis
• Tubular atrophy shrinkage of renal parenchyma
• Interstitial infiltrate plasma cells,
  Eosinophils

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Transplant rejection

• Increased graft survival
• Minimizing HLA disparity
• Class I class II matching
• Immunosuppresive therapy
• Azathioprine, steroids, cyclosporine
• Infections, EBV induced lymphoma, HPV induced
  squamous cell carcinoma, Kaposis sarcoma

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Bone marrow Transplantation

• Hematological malignancy
• Aplastic anemia
• Immunodeficiency
• Major problems
• Graft Versus Host (GVH) disease
• Transplant rejection

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Graft Versus Host (GVH) disease

• Immunologically competent cells or their
  precursor are transplanted into immunologically
  crippled recipient
• Bone marrow Transplantation
• Liver transplant
• Immunocompetent T cell derived from donor marrow
  recognizes recipient HLA as foreign react

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Acute Graft Versus Host (GVH) disease

• Occurs within days/ weeks of allogenic BMT
• Mainly affects immune system, epithelia of
  skin, liver intestine
• Infection CMV induced pneumonitis
• Skin rashes, desquamation
• Liver jaundice
• Intestine ulceration, bloody diarrhea
• Direct cytotoxicity by CD8 T cells cytokines
  released by donor T cells

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Chronic Graft Versus Host (GVH) disease

• Extensive cutaneous injury
• Destruction of appendages
• Dermal fibrosis
• Cholestatic jaundice
• Esophageal stricture
• Recurrent infection
• Depletion of donor T cells before transfusion
  eliminate GVHD

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Systemic Lupus Erythematosis (SLE)
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Systemic Lupus Erythematosis

• Multisystem disease of AI origin, characterized
  by presence of Antinuclear Antibodies (ANA)
• Acute or insidious in onset
• Chronic remitting relapsing febrile illness
• Principally affects skin, joints, kidney
  serosal membrane

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Systemic Lupus Erythematosis

• American Rheumatism Association
• 1997 revised 11criterias for SLE

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SLE 1997 Revised criterias

• Malar rash Fixed erythema over malar eminence
• Discoid rash E. raised patches with aderent
  keratotic scaling follicular plugging
• Photosensitivity skin rash after UV light
  exposure
• Oral ulcers painless oral / nasopharyngeal
  ulcers
• Arthritis nonerosive arthritis involving 2 or
  more joints
• Serositis pleuritis /pericarditis
• Renal disorder persistent proteinuria gt0.5 g/dl
• Cellular cast

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SLE 1997 Revised criterias

• Neurological disorder
• Seizures in the absence of offending drug/
  metabolic disorder
• 9. Hematological disorder
• psychosis
• Hemolytic anemia with reticulocytosis
• Leukopenia - lt 4000/mm3
• Lymphopenia lt1500/mm3
• Thrombocytopenia - lt1.0 lakh /mm3
• 10. Immunological disorder
• Anti ds DNA, anti sm / or antiphospholipid
• 11. Antinuclear antibody (ANA)
• Abnormal titre of ANA in the absence of drug
  induced SLE

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Systemic Lupus Erythematosis

• Etiology pathogenesis
• Failure of self tolerance mechanisms
• Genetic factors
• Environmental factors
• Immunological mechanism

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Systemic Lupus Erythematosis

• Genetic factors
• Family members have risk of developing SLE
• Upto 20 of clinically unaffected I0 relative
  show ANA
• High rate of concordance in monozygotic twins
• MHC genes regulate production of autoantibody

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Systemic Lupus Erythematosis

• Environmental factors
• Drugs Hydralazine, Procainamide, D
  pencillamine can induce SLE like lesions
• UV light exacerbate the disease
• Sex hormones SLE 10 times more common in
  females than males

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Systemic Lupus Erythematosis

• Immunological factors
• CD4 T helper cells
• B cells
• Most of visceral lesions Type III reactions
• Auto antibodies against red cells, WBC platelet
  mediate their effect by Type II reaction

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SLE - ANA

• Anti- Nuclear Antibody (ANA)
• Major pathogenetic significance
• Diagnosis management of SLE patients
• Four types
• Ab to DNA
• Ab to Histone
• Ab to nonhistone proteins bound to RNA
• Ab to nucleolar AG

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SLE - ANA

• Indirect Immunoflurorescence used for detection
  of ANA
• Four basic staining pattern
• Homogenous/ diffuse nuclear staining
• Ab to chromatin histone
• Peripheral staining
• Ab to double stranded DNA
• Speckled pattern least specific
• Nucleolar pattern Ab to nucleolar RNA

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Homogenous/ diffuse
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Peripheral
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Speckled
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Nucleolar
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SLE - ANA

• IIF test for ANA is positive in all SLE patients
  
• Highly sensitive
• Not specific
• Ab to Double stranded DNA Smith (sm) Ag
  Diagnostic of SLE
• Others Anti histone, nuclear RNP, SS-A, SS-B,
  scl- 70

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SLE

• LE cell
• Phagocytic leukocyte (neutrophil /macrophage)
  that engulfed the denatured nucleus of an injured
  cell

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LE CELL
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SLE

• LE cell preparation
• Agitation of blood rupture of leukocytes
  exposes nuclei to ANA
• Loss of chromatin pattern homogenous basophilic
  body (LE body/ Hematoxylin body)
• Compliment fixation renders Ab coated nuclei for
  phagocytosis
• Seen in pericardial / pleural effusion

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SLE Clinical features pathologic manifestation

• Hematologic 100
• Arthritis 90
• Skin 85
• Fever 83
• Fatigue 81
• Weight loss 63
• Renal 50
• CNS 50
• Pleurits 46
• Pericarditis 33

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SLE - Morphology

• Immune complex disease Blood vessel, kidney,
  connective tissue skin
• Acute necrotizing vasculitis small vessels
  arterioles
• Chronic stage fibrous thickening with luminal
  narrowing

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SLE - Kidney

• All SLE patient show lesion in kidney
• WHO 5 types of lupus nephrits
• Class I Normal by light M/s, EM IF
• Class II Mesangial lupus GN
• Class III Focal proliferative GN
• Class IV Diffuse proliferative GN
• Class V - Membranous GN

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Mesangial lupus GN

• 10- 25 patients
• Mild hematuria/trasient proteinuria
• Increase in mesangial matrix cells
• Granular mesangial deposits of Ig complement
  are always present

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Focal proliferative GN

• 20-35 of patients
• Focal lesion, affecting less than 50 of the
  glomeruli
• Swelling proliferation of endothelial
  mesangial cells
• Neutrophils
• Fibrinoid deposits intra capillary thrombi
• Hematuria proteinuria

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Diffuse proliferative GN

• Most serious renal lesion
• 35- 60 of patient
• Proliferation of endothelial, mesangial cells
  epithelial cells producing epithelial crescent
• Fibrinoid necrosis leukocyte infiltration
• Most or all glomeruli are involved
• Gross hematuria proteinuria
• Nephrotic syndrome 50

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Diffuse proliferative GN

• EM subendothelial deposits
• Homogenous thickening of capillary wall Wire
  loop lesion

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Membranous GN

• 10- 15 of patients
• Thickening of capillary wall
• Severe proteinuria - nephrotic syndrome
• EM subepithelial deposits of immune complex

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SLE - SKIN

• Malar rash 50 cases
• Exposure to sunlight accentuates the erythema
• Liquefactive degeneration of basal layer
• Edema, perivascular infiltrate
• Vasculitis fibrinoid necrosis of vessels
• Ig complement deposition along dermo-epidermal
  junction

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SLE - Joints

• Non erosive synovitis with little deformity
• Neutrophilic infiltration fibrin synovium
• Perivascular mononuclear infiltrate in
  subsynovial tissue

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SLE - CNS

• Acute vasculitis
• Non inflammatory occlusion of small vessel by
  intimal proliferation
• Antiphospholipid Ab