Chronic Antibody Mediated Rejection: Fact or Fancy

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Chronic Antibody Mediated RejectionFact or
Fancy?

• Robert B. Colvin, M.D.
• Harvard Medical School
• Massachusetts General Hospital
• 8th Banff Conference
• Edmonton
• July 17, 2005

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CAN

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Chronic Rejection

• Chronic slow process, but active
• Rejection injury from alloimmune
• mechanisms (antibody, T cells)
• Distinguished from non-alloimmune mech. of late
  graft injury

Pace of progression Time of onset
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(No Transcript)
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Chronic Allograft Glomerulopathy (CAG)
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Lamination of capillary basement membranes C4d
Chronic Rejection, DSA (class II) 2.5 yrs post-tx
Glomerulus
Peritubular Capillary
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Evidence for Antibody Mediated Chronic Rejection
in vivo
Circulating anti-HLA antibodies correlate
with late graft loss in humans
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DSA Precede Graft Loss

• De novo DSA in 51 of 112
• patients with graft failure
• vs. 2 of 123 stable controls
• over 5 years
• Usually preceded graft
• failure (60)

Worthington et al (Manchester UK) Transplant
751034, 2003
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Frequency of HLA antibodies

• Kidney 20.9
• Liver 19.3
• Heart 22.8
• Lung 14.2
• 4763 patients from 36 centers
• Terasaki and Ozawa AJT, 4438, 2004

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Antibodies Predict Graft Failure
Prospective trial 2278 kidney recipients in 23
centers HLA antibodies N One year
Graft failure Yes 500 6.6 No
1778 3.3 (p lt 0.001) De novo HLA
Ab Yes 244 8.6  No 1421 3.0
(p 0.00003)
Excess loss due to Ab 3-5/year

• Terasaki and Ozawa, AJT, 4438, 2004

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• Tenuous link between DSA and graft pathology in
  past--
• Little or no IgG, C3, EM deposits
• Now endothelial C4d provides strong evidence for
  recent antibody activity in tissue

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DSA usually found in patients with C4d CR/CAN

• with DSA
• C4d C4d-
• 88 0 Mauiyyedi 2001
• 100 21 Cardarelli 2005
• 63 17 Herman 2005

plt0.0110.001
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DSA in graft not always detected in blood

• 20 Pts with CAN late rejection
• with DSA
• At time of Graft Nx Post Nx
• Blood Graft Eluate Blood
• 32 71 73

Martin et al (Dijon) Transplant 76395, 2003
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C4d PTC in Chronic Rejection

• N
• Chronic Rejection (CAG/CAA) 147 50
• Mauiyyedi (Boston) 2001 CAA/CAG 38 61
• Regele (Vienna) 2002 CAG 58 67
• Mróz (Warsaw) 2003 CAA/CAG 6 83
• Vongwiwatana (Edmonton) 2004 CAG 24 25
• Sijpkens (Leiden) 2004 CAG (Glom C4d) 10 40
• Herman (Leuven Bel) 2005 CAG 11 73
• Jeong (Seoul) 2005 CAA 24 21
• Control Tx (No CAG/CAA) 247 15
• Mauiyyedi (Boston) 2001 30 3
• Regele (Vienna) 2002 155 22
• Mróz (Warsaw) 2003 13 8
• Vongwiwatana (Edmonton) 2004 (IgAN) 19 0
• Sijpkens (Leiden) 2004 14 7
• Jeong (Seoul) CIT 16 6

85/17115.3 38/24815.3
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Pathology associated with C4d PTC in late renal
tx bx (gt12 mo)

• Chronic allograft glomerulopathy
• 18 C4d Glomeruli
• Lamination of PTC basement membranes
• Mononuclear cells in PTC
• Not associated with acute rejection,
  endarteritis, thrombi, polys (acute rej), Banff
  CAN or intimal fibrosis
• Later C4d- in 38 (gt6mo)

Regele et al (Vienna) JASN 132371,2002
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21248648
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2.5 yr post-tx Anti-donor class II
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Other features of C4d late rejection

• Glomerulitis (mononuclear cells)
• Glomerular C4d with Neg PTC
• Sijpkens (Leiden) 2004
• Plasma cell infiltrate
• 52 vs 16 Poduval (Chicago) 2005

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C4d CAG with Glomerulitis
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Chronic allograft glomerulopathy C4d glom, C4d-
PTC, DSA
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Chronic humoral rejection Plasma cells
21216348
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Does acute antibody mediated rejection lead to
chronic injury (CAN)?
Sometimes
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3 weeks later (Nx)
2 wk bx C4d
M Mengel Hanover
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C4d CAN

• C4d AHR
• ? Graft loss due to CAN (60 vs 30 - 2 yrs)
• Transplant glomerulopathy and macrophages
  predicted graft failure

SmavatkulSamaniego, (Wisc), ATC Abstr 619, 2005
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C4d deposition predicts TG and CAN
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Reasons for C4d Negative PTC Transplant
Glomerulopathy/CAG

• 1. Technical/sampling
• Glomeruli can be positive with PTC -
• Capillaries disappear in CAN
• 2. T cell mediated TG/CAG
• 3. Other cause of TG/CAG
• Thrombotic microangiopathy (CIT)
• Immune complex GN/HCV
• 4. Left over from prior episode of CHR (inactive)

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PTC density (CD34) correlates inversely with
serum Cr
Shimizu et al KI 2005
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Reasons for C4d Negative PTC Transplant
Glomerulopathy/CAG

• 1. Technical/sampling
• Capillaries disappear in CAN
• Glomeruli positive with PTC-
• 2. T cell mediated TG/CAG
• 3. Other causes of TG/CAG
• Thrombotic microangiopathy (CIT)
• Immune complex GN/HCV
• 4. Left over from prior episode of CHR (inactive)

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Antibody may fluctuate Episodic
C4d/injury/repair
DSA Conc
Time
PTC C4d BM
- - - -
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Is C4d always bad?
No

• C4d in 7 day protocol bx correlated with
• rejection (33 vs 3) and DSA
• but not outcome at 1 yr
• (even without specific rx)
• Koo et al (Oxford) Transplantation 78398, 2004
  (N48)

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Normal Protocol Biopsy with C4d
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Protocol Bx-- Mild glomerulitis, PTC mono, C4d
4905
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C4d in Stable Renal Allografts

• Protocol biopsies 1-12 mo.
• N C4d
• Mengel et al (Hanover)
• AJT, 5 1050, 2005 501 2-4
• Grande et al (Mayo)
• AJT 4101, 2004
• ABO incompatible 16 25

Harbinger of rejection or accommodation?
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• "modification of therapy based solely on the
  finding of C4d should be discouraged, as such
  modifications could disrupt accommodation and
  thus do more harm than good
• Williams (Mayo) Transplant 78 1471, 2004

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Evidence for Peritubular Capillary Endothelial
Accommodation in vivo

• ? bcl-xL in DSA recip
• Salama (Hammersmith) Am J Transplant 1260,
  2001
• ? CD59, CD55 in chronic rejection
• Cornell (Boston), Mod Pathol 17 285A, 2004
• C4d without C5b pig to baboon xenografts
• Williams (Mayo) Transplant 78 1471, 2004

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Why doesnt complement fixation elicit acute
inflammation in these settings?
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Acute Rejection

• T cells Antibody

Chronic Rejection
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Stable
Acute
Chronic
Accommodation strength
Rejection strength
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Takemoto et al, Am J Transplant, 41033, 2004
Colvin and Smith, Nature Immunol Rev, in press
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Postulated Stages of Humoral Rejection



I

II

III

IV






Clinical graft dysfunction


Graft pathology


Trans
-

Graft C4d

plant



Blood de novo antibodies




Time (not to scale)


Graft


loss


Accommodation
Rejection
Clinical
Subclinical
No C4d
With C4d
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• The emerging message is that donor specific
  antibody can mediate a number of clinical
  rejection syndromes
• Halloran AJT 3639, 2003

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The newly described C4d conditions do not fit
into current Banff categories Acute
antibody-mediated rejection CAN Normal Other (not
due to rejection)
Racusen et al, Am J Transplant 3708, 2003
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Why do we need new disease categories?

• Distinct pathologic features
• Distinct clinical features
• Distinct treatment
• Frequency of a disease is not a criterion

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Three Antibody Mediated Conditions

• Acute Accommodation Chronic
  Ab Med Rej to Ab Ab Med
  Rej
• C4d
• DSA (-) (-) (-)
• Clinical Rapid ?Cr No ? Cr
  Slow ?Cr
• Pathology Polys, necr, None CAG, CAA
• thromb/hmx ML PTC
• ATI Fibrosis/TA
• Treatment Yes! Aggressive ? No Yes
  ?Anti-B/PC

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This is what we (Banff) have for Antibody
mediated injury Acute antibody-mediated
rejection in renal allografts

• Morphologic evidence of acute tissue injury, such
  as
• acute tubular injury
• neutrophils and/or mononuclear cells in
  peritubular capillaries and/or glomeruli, and/or
  capillary thrombosis or
• intimal arteritis/fibrinoid necrosis/intramural
  or transmural inflammation in arteries.
• Immunopathologic evidence for antibody action,
  such as
• C4d and/or (rarely) immunoglobulin in
  peritubular capillaries or immunoglobulin and
  complement in arterial fibrinoid necrosis.
• Serologic evidence of circulating antibodies
  to donor HLA or other
  anti-donor endothelial antigens

Racusen et al, Am J Transplant 3708, 2003
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Draft Banff 2005 criteria for Chronic (active)
antibody-mediated rejection in renal allografts

• Morphologic evidence of chronic tissue injury,
  such as
• GBM duplication
• Lamination of PTC BM
• Arterial intimal fibrosis
• Interstitial fibrosis/tubular atrophy
• Immunopathologic evidence for antibody activity,
  such as
• C4d in peritubular capillaries and/or glomeruli
  (paraffin)
• and/or (rarely) immunoglobulin
• Serologic evidence of circulating antibodies to
  donor HLA or other anti-donor endothelial
  antigens
• Clinical evidence of chronic graft dysfunction

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CLINICAL CHRONIC ANTIBODY-MEDIATED REJECTION

• Graft Dysfunction
• Graft pathology
• Graft C4d
• Blood DSA

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SUBCLINICAL CHRONIC ANTIBODY-MEDIATED REJECTION

• No Graft Dysfunction
• Graft pathology
• Graft C4d
• Blood DSA

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ACCOMMODATIONWITH COMPLEMENT DEPOSITION IN GRAFT

• No Graft Dysfunction
• No Graft pathology
• Graft C4d
• Blood DSA

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ACCOMMODATIONWITHOUT COMPLEMENT DEPOSITION IN
GRAFT

• No Graft Dysfunction
• No Graft pathology
• No Graft C4d
• Blood DSA

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Proposed New Banff Categories

• Chronic (active) antibody-mediated rejection
• Clinical
• Subclinical
• Accommodation to donor reactive antibodies
• With complement deposition
• Without complement deposition