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 •
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
chronic transplant rejection
Pathology related to cytokine production by CD4 T
cells
• Atherosclerosis of vascular endothelium with
proliferation of intimal smooth muscle cells • Obliterated vascular lumens by proliferating smooth
muscle cells • Duplication of basement membranes • Interstitial fibrosis with tubular atrophy (thyroidization) • Glomerular sclerosis/hyalinization • Plasma cells and eosinophils in interstitium
criteria for chronic antibody-mediated rejection (AMR)
Immunopathology
• C4d deposition in peritubular capillaries and/or
glomeruli
• Serology
• Anti-donor HLA or other endothelial antigens
Hematopoietic steam cell transplant (HSCT)
• Most important factor in graft survival is
HLA compatibility
• Source
• Bone marrow : HLA match A, B, C, DQ, DR •
• Peripheral blood after administration of hematopoietic growth factors (G-CSF) • HLA match A, B, C, DQ, DR •
Umbilical cord blood: HLA match A, B, DR
Recipient undergoes chemotherapy &/or radiation to wipeout
bone marrow
HSCT - risks
Marrow also vulnerable to rejection
• Early or late graft failure • DNA analysis BM to assess donor and recipient
populations
• Risks
• Graft-versus-Host Disease (GvHD) • Immune deficiency
• Opportunistic infections
GVHD
Donor derived immunocompetent T lymphocytes recognize recipient’s HLA antigen as foreign and react against them • Can RARELY occur in solid organ transplants (liver with
lymphoid cells) • More pronounced in allogeneic HSC transplants • History of transfusion with non-irradiated blood products (TA
-GvHD)
• Marrow failure (pancytopenia) can be fatal
• Recipient’s incompatible HLA antigen recognized as foreign by
donor cells
• Example: Donor is homozygous HLA-A1,-B2 Recipient is HLA-A1, -A2, -B2 Donor sees HLA-A2 as foreign
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
SKIN GVHD
presents with skin rash
Spongiosis, early bulla formation, vacuolar degeneration of basal layer Mononuclear cells and lymphocytes around apoptotic keratinocytes satellitosis
If severe and diffuse, can lead to widespread sloughing (epidermolysis)
GI GVHD
resents with bloody diarrhea
Apoptosis due to cytokine production by CD4+ T cells and direct cytotoxicity by CD8+ T cells
Necrosis of colonic epithelium with necrotic
intraluminal epithelial cells indicative of severe GVHD
Liver GVHD
presents with jaundice
Periportal mononuclear infiltrate
Reactive bile duct epithelium with partially necrotic and sloughed lining cells
Cholestasis with bile pigment in ductules – clinically associated with jaundice; lab hyperbilirubinemia
