Transplant Immunology &
Renal Allograft Rejection
Shehzad Rehman, MD
Assistant Professor
Division of Nephrology, Hypertension and Renal
University of Florida
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
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
Human Chromosome 6
• 2 types of HLA
Class I
Class II
Slide courtesy Dr. Casey
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
Mechanisms of Rejection
• Cellular and antibody-mediated components
• Two stages
– Sensitization stage
– Effector stage
• Two kinds of response
– Amnestic response
– Anamnestic response
Sensitization Stage
• T-Cell receptors (TCRs) recognize foreign
• 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
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
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
Second Messenger Systems
• Inositol phospholipid → IP3 & DAG
• This leads to intracellular Ca2+ release
• Ca2+-calmodulin complexes form, triggering
second messenger systems
– Calcineurin → NFAT
– NFκB
• These bind to the IL-2 gene and promote IL-2
transcription via mRNA
Effector Stage
• IL-2 and other cytokines promote
inflammation and proliferation
• Signal 3
• β-chemokines cause macrophage infiltration
• Growth factors cause fibrosis and vascular
• Final common pathway is cell apoptosis
Halloran, N Eng J Med; 351:3715, 2004
• Acute rejection can be classified based on
various patterns:
– Time of onset: early vs. late
– Pathogenetic mechanisms: antibody-mediated or
– Clinical/histological features: hyperacute,
accelerated, acute, chronic.
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.
Afferent arteriolar thrombosis in a case of hyperacute rejection
This small artery in a patient with hyperacute rejection is almost
occluded by a fibrin thrombus
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.
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 antibodymediated, or both.
• Classified according to Banff Schema (Solez et
al., Am J Transplant, 2008).
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).
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).
Moderate interstitial mononuclear inflammation affecting 25-50% of the
sampled parenchyma (grade i2)
Banff IA: Moderate tubulitis with 5-10 mononuclear cells per tubular cross
Banff IB: Severe tubulitis with greater than 10 mononuclear cells per tubular
cross section.
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
• Banff III: severe vascular rejection
– Transmural arteritis and/or arterial fibrinoid
changes and smooth muscle necrosis.
Banff IIA: Mild intimal arteritis with rare subendothelial mononuclear cells.
Banff IIB: Moderate intimal arteritis with numerous subendothelial
mononuclear cells.
Banff III: Severe intimal arteritis with transmural inflammatory infiltration,
fibrinoid change and myocyte injury.
• 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.
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
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”.
Aggregates of mononuclear inflammatory cells in dilated
peritubular capillaries, scored as ptc3
Transplant glomerulitis with infiltrating mononuclear
inflammatory cells (arrows) within capillary loops
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.
C4d staining: immunohistochemistry vs.
• Treatment of AMR is not well defined.
• Options include:
– Plasmapheresis
– Rituximab
• Newer options include agents under study e.g.
bortezomib, eculizumab.
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.
Chronic Rejection
• Some features remain consistent with chronic
immune injury:
– Transplant glomerulopathy with doublecontouring
– Certain vascular changes (disruptions of the
elastica, inflammatory cells)
Chronic transplant glomerulopathy with numerous double
contours (arrows) in glomerular basement membranes
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
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
• Timing of rejection (Sijpkens, Transplantation,
– 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.
Implications of Rejection
• Data presented at ATC 2011 suggested
interstitial inflammation is a worse
• Newer data suggested vascular rejection may
not carry the same grim prognosis in modern
• Worse prognosis for AMR.

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