transplant immunology & renal allograft rejection shehzad rehman, md assistant professor...
TRANSCRIPT
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Transplant Immunology &Renal Allograft Rejection
Shehzad Rehman, MDAssistant Professor
Division of Nephrology, Hypertension and Renal Transplantation
University of Florida
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HLA: Introduction
• Main barrier to transplantation is Major Histocompatibility Complex (MHC)
• MHC in humans is known as Human Leukocyte Antigen (HLA)
• Short arm of chromosome 6• Inherited as 2 haplotypes (half-sets), one from
each parent
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Types of HLA
• Class I and class II• Class I: A, B, C• Class II: DR, DP, DQ• Important for transplant: A, B, DR• Numbered sequentially• Typical: A2, A23; B7, B13; DR3, DR7
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Human Chromosome 6
• 2 types of HLA
Class IHLA
Class IIHLA
Slide courtesy Dr. Casey
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Human Leukocyte Antigen
• Class I HLA – expressed on all nucleated cells– presents antigen to cytotoxic CD8(+) T cells which
induce cell death• Class II HLA – expressed only on antigen-presenting cells (APCs)– presents to helper CD4(+) T cells which activate
macrophages, B cells, effector T cells
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Mechanisms of Rejection
• Cellular and antibody-mediated components• Two stages– Sensitization stage– Effector stage
• Two kinds of response– Amnestic response– Anamnestic response
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Sensitization Stage
• T-Cell receptors (TCRs) recognize foreign antigens
• Two signals needed:– Signal 1: HLA interacts with TCR (CD3)– Signal 2: Costimulation: CD28 with CD80 or CD86;
or CD40 with CD40L• Absence of costimulation may lead to clonal
anergy
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Sensitization: Direct Pathway
• Donor APCs carried over on graft present antigens to host T-cells
• Usual APCs are dendritic cells• Important and dominant in early, acute
rejection processes
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Sensitization: Indirect Pathway
• Host APCs ingest and present allopeptides to host T-cells
• Lead to T-cell proliferation• Important in late/chronic processes• Also important in antibody-mediated rejection
processes
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Second Messenger Systems
• Inositol phospholipid → IP3 & DAG• This leads to intracellular Ca2+ release• Ca2+-calmodulin complexes form, triggering
second messenger systems– Calcineurin → NFAT– PKC– NFκB
• These bind to the IL-2 gene and promote IL-2 transcription via mRNA
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Effector Stage
• IL-2 and other cytokines promote inflammation and proliferation
• Signal 3• β-chemokines cause macrophage infiltration• Growth factors cause fibrosis and vascular
damage• Final common pathway is cell apoptosis
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Halloran, N Eng J Med; 351:3715, 2004
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Classification
• Acute rejection can be classified based on various patterns:– Time of onset: early vs. late– Pathogenetic mechanisms: antibody-mediated or
cellular– Clinical/histological features: hyperacute,
accelerated, acute, chronic.
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Hyperacute Rejection
• Irreversible antibody-mediated rejection, occurring in minutes-to-hours.
• Preformed donor-specific antibodies.• Can also be due to ABO-incompatibility.• Immediate antigen-antibody binding with
complement activation.• Very rare in the post-crossmatch era.• Histology: intense engorgement of the glomerular
and peritubular capillaries with RBC clumping and fibrin thrombi.
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Afferent arteriolar thrombosis in a case of hyperacute rejection
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This small artery in a patient with hyperacute rejection is almost occluded by a fibrin thrombus
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Accelerated Rejection
• Usually due to presensitization.• Presents several days after transplantation.• Usually represents an anamnestic reponse,
resulting in rapid production of antibodies after exposure.
• Rejection starts after antibodies reach a critical level.
• Can be avoided with attention to crossmatch.
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Acute Rejection
• Most commonly seen clinically.• Can happen anytime, but 75% are seen within
the first 3 months.• 10-20% of develop AR in first 12 months.• T-cell-mediated (cellular), B-cell or antibody-
mediated, or both.• Classified according to Banff Schema (Solez et
al., Am J Transplant, 2008).
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Acute Cellular Rejection
• Generally T-cell mediated.• Activated via alloantigen-dependent
mechanisms (classic antigen-presentation and 3-signal model).
• Can also be via non-alloantigen-dependent pathway (innate immunity: TLRs and NK cells).
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Acute Cellular Rejection
• Borderline changes:– Either tubulitis with <25% parenchymal
inflammation or infiltration with 1-4 cells/tubule• Banff I: tubulointerstitial inflammation only
with >25% parenchymal involvement.– IA: moderate tubulitis (5-10 cells/tubule).– IB: severe tubulitis (>10 cells/tubule).
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Moderate interstitial mononuclear inflammation affecting 25-50% of the sampled parenchyma (grade i2)
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Banff IA: Moderate tubulitis with 5-10 mononuclear cells per tubular cross section
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Banff IB: Severe tubulitis with greater than 10 mononuclear cells per tubular cross section.
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Acute Cellular Rejection
• Banff II: vascular rejection– IIA: Mild-to-moderate intimal arteritis (<25%
luminal involvement in at least 1 artery)– IIB: Severe intimal arteritis (>25% luminal
involvement)• Banff III: severe vascular rejection– Transmural arteritis and/or arterial fibrinoid
changes and smooth muscle necrosis.
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Banff IIA: Mild intimal arteritis with rare subendothelial mononuclear cells.
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Banff IIB: Moderate intimal arteritis with numerous subendothelial mononuclear cells.
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Banff III: Severe intimal arteritis with transmural inflammatory infiltration, fibrinoid change and myocyte injury.
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Treatment
• Borderline: based on clinical and pathological picture. Some advocate no treatment.
• Banff IA: generally steroid pulse.• Banff IB: steroid pulse and/or ATG.• Banff II/III: ATG• Banff II & III may also require treatment for
possible concurrent AMR.
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Antibody-Mediated Rejection
• Antibodies can target the capillary endothelium, leading to complement fixation.
• This causes inflammation and endothelial injury capillary endothelialitis
• Complement activation leads to increased presence of terminal products of complement cascade C4d.
• Can uncommonly be due to non-anti-HLA antibodies.
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Antibody-Mediated Rejection
• According to Banff, diagnosis of AMR requires:– Presence of circulating donor-specific antibodies.– C4d+– Morphologic evidence of acute tissue injury:• ATN-like minimal inflammation• Capillary and/or glomerular inflammation (PTC/G)• Arteritis (v3)
• If either C4d or DSA are absent, Banff classifies as “suspicious for AMR”.
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Aggregates of mononuclear inflammatory cells in dilated peritubular capillaries, scored as ptc3
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Transplant glomerulitis with infiltrating mononuclear inflammatory cells (arrows) within capillary loops
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Acute humoral rejection in a human renal allograft. PAS staining shows the presence of a sparse interstitial infiltrate of neutrophils, together with edema.
C4d deposition in peritubular and glomerular capillaries. An immunohistochemical stain using polyclonal rabbit antibodies that are specific for C4d shows C4d deposition.
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C4d staining: immunohistochemistry vs. immunocytochemistry/immunofluorescence
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Treatment
• Treatment of AMR is not well defined.• Options include:– ATG– IVIG– Plasmapheresis– Rituximab
• Newer options include agents under study e.g. bortezomib, eculizumab.
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Chronic Rejection
• The term “chronic rejection” was previously used to describe all manner of chronic changes in the allograft, on the assumption that they were immune-mediated.
• As non-immune factors became known, the term “chronic rejection” has fallen out of favor, to be replaced by chronic allograft nephropathy, and now, interstitial fibrosis/ tubular atrophy.
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Chronic Rejection
• Some features remain consistent with chronic immune injury:– Transplant glomerulopathy with double-
contouring– Certain vascular changes (disruptions of the
elastica, inflammatory cells)
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Chronic transplant glomerulopathy with numerous double contours (arrows) in glomerular basement membranes
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Implications of Rejection
• Certain clinical features have important implications in acute rejection.
• Presence of rejection.– Grafts have a longer half-life in patients who never had an
acute rejection (Hariharan, N Engl J Med, 2000; Flechner, Transplantation, 1996).
– If fully reversible, may not have a deleterious effect on graft function in the long-term (Opelz, Transpl Proc, 1997; CTS 6-year data):• 60% vs. 75% for treatment for rejection.• 73% vs. 75% for those whose S/Cr returned to normal (<1.5 mg/dL)
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Implications of Rejection
• Number of rejections (Dickenmann, Transpl Int, 2002; Pascual, N Engl J Med, 2002).– Better with single episode than with 2 or more
episodes.• Timing of rejection (Sijpkens, Transplantation,
2003).– 10-yr death-censored graft survival 86% for AR <3
months vs. 45% for AR >3 months• Severity of rejection.– Correlation between Banff grade and outcome.
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Implications of Rejection
• Data presented at ATC 2011 suggested interstitial inflammation is a worse prognosticator.
• Newer data suggested vascular rejection may not carry the same grim prognosis in modern era.
• Worse prognosis for AMR.