Transplant Immunology Flashcards
Types of grafts
Autograft
Isograft
Allograft
xenograft
factors in graft viability/survival
- ABO blood group compatibility between recipient and donor
- most important requirement for organ transplant success
- preformed ant-HLA cytotoxic antibodies in graft recipients
- HLA antibody sources: previous grafts, pregnancy, transfusions
- close match of HLA-A HLA-B HLA-C AND HLA-DR loci between donors and recipients desirable
Hyperacute rejection
IRREVERSIBLE reaction within minutes or hours after transplant • Organ must be removed • Type II hypersensitivity reaction
• Pathogenesis
• Immunoglobulin and complement targeting endothelium of small vessels
(capillaries, arterioles) • Neutrophilic influx with fibrinoid necrosis and vessel thrombosis with
infarct
• Causes
• ABO incompatibility (A recipient receives kidney from B donor)
• Reaction between preformed anti-HLA antibodies in recipient directed
against the donor HLA antigens in vascular endothelium
• Uncommon due to pre-transplantation screening (0.5%
incidence)
Mechanism of hyperacute rejections
- Preformed anti-donor antibody
- Complement activation
- Neutrophil margination , endothelial damage
- Inflammation
- Thrombosis formation and necrosis of teh Bessel
translated kidney displays mottled cyanosis and diminished turgor in graft
DIF: glomerular capillary loops show strong staining in igG
immunoglobulin and complement deposits in glomeruli, peritubular capillaries and interlobular arters
cells infiltrate the glomerulus
afferent arteriolar thrombosis is a case of hyper acute rejction
fiber throbs acceding small artery
BANFF 2017 KIDNEY MEETING REPORT
Category 1: Normal biopsy or nonspecific changes
- Category 2: Antibody‐mediated change
- Active ABMR
- Chronic active ABMR
- C4d Staining without Evidence of Rejection
• Category 3: Borderline changes
- Category 4: TCMR
- Acute TCMR
- Chronic Active TCMR
Acute humoral rejection
- • Rejection vasculitis (transmural)
- PMN infiltrate w/ endothelial cell necrosis
- Immunoglobulin deposition & complement
- Fibrin deposition thrombosis
- • Mediated by anti-donor antibodies
- Post-transplant sensitization
- Cessation of immunosuppressives
- • If repeated episodes of tissue infarction
- Renal cortical atrophy
• Vasculitis of graft vessels
- Lymphocytes infiltrating through vessel wall
- Leading to vascular thrombosis
- Infarct of cortex
- Humoral mediated immune reaction
- Associated with circulating donor-specific alloantibodies (DSA)
- Immunological evidence of antibody-mediated process (C4d+) • Positive peritubular capillary C4d indicative of humoral component
• May lead to graft failure
Arteritis with transmural inflammatory infiltration and fibrinoid change
Immunoflourescence Cd4 staining in a renal transplant biopss
immunoflurescnece with CD4 monoclonal antibody demonstrating diffuse and strong pertubular capillary deposition in a renal transplant biopsy . The yellow staining indicates CD4 deposition. this is consistent with antibody mediated rejection
Acute cell mediated rejection
Activation of both CD4+ and CD8+ T cells
• CD8+ cells damage tubules and endothelial cells (cytotoxicity)
• Endotheliitis not vasculitis with intimal arteritis (subendothelial
infiltration by mononuclear cells) • Responds promptly to immunosuppressive therapy
• CD4+ cells release cytokines, activate macrophages and B cells
• Lymphocytes invading tubules (“tubulitis”) and
endothelialitis • Tubulitis (infiltration by > 4 mononuclear cells / tubular cross-section)
• Reversible with immunosuppressants such as OKT3
and cyclosporine
acute T-cell mediated (cellular) rejection of a kidney allograft
inflammatory cells in intersitium and between epithelial cells of the tubules
rejection vasculitis with inflammatory cells attacking and undermining endothelium (endothelitis)
Humoral vs cell mediated rejection
Humoral
• Vasculitis
• C4d & DSA +
• Cell
• Interstitial and tubular lymphocytic
inflammation & endotheliitis
acute transplant rejection
Potentially reversible with immunosuppressive therapy if mainly
acute cellular rejection
- Therapeutic options for Antibody Mediated Rejection include
- Intensification of maintenance immunosuppression • Plasmapheresis/plasma exchange • Intravenous immune globulin (IVIG) • Steroids • Antilymphocyte antibodies (if concurrent cellular rejection) • Adjunctive agents: rituximab, bortezomib, eculizumab, also splenectomy
- Risks of immunosuppressive therapy
- Cervical squamous cell carcinoma • Malignant lymphoma (usually B-cell type) • Squamous cell carcinoma of the skin (most common)
Immunosuppressive therapy
- Cyclosporine
- Blocks activation of transcription factor for IL-2 (IL-2 serves as a T-cell recruiter)
• Tacrolimus
• Inhibits T cells by i nhibition of the phosphatase calcineurin, which is required for activation
of a transcription factor called nuclear factor of activated T cells (NFAT). NFAT stimulates transcription of cytokine genes, in particular, the gene that encodes IL-2.
- Azathioprine
- Inhibits leukocyte development in bone marrow
Corticosteroids
• Anti-inflammatory (inhibits arachadonic
Most patients acid synthesis)
are on at least 2 of these • No leukotrienes; no prostaglandins Rx’s.
- Rapamycin
- Inhibits cytokine driven lymphocyte proliferation
- Anti-CD3 (Monoclonal Ab) (OKT3)
- Blocks T cell activation, opsonization of T cells
• Mycophenolate mofetil: inhibits lymphocyte proliferation
cyclosporine
Blocks activation of transcription factor for IL-2 (IL-2 serves as a T-cell recruiter)
tacrolimus
Inhibits T cells by i nhibition of the phosphatase calcineurin, which is required for activation
of a transcription factor called nuclear factor of activated T cells (NFAT). NFAT stimulates transcription of cytokine genes, in particular, the gene that encodes IL-2.
Azathioprine
Inhibits leukocyte development in bone marrow •
Acute GVHD
During first 100 days/3 months post transplant “GVHD Triad”:
• Dermatitis (rash)
• Hepatitis (jaundice)
• Gastroenteritis (abdominal pain, diarrhea) Result of direct cytotoxicity by CD8+ T cells and cytokines released by the sensitized donor T cells
