Complement in Heart Allograft Biopsies

1
Complement in Heart Allograft Biopsies
E. Rene Rodriguez W. M. Baldwin, III
2
(No Transcript)
3
(No Transcript)
4
Variables in Heart Studies
Patient Population

• Percent Sensitized
• LVAD
• Blood Transfusions
• Pregnancy
• Previous transplant

Immunosuppression
5
Prospective Study of Cardiac Transplants

• All biopsies from Jan 01 to Dec 03
• 665 biopsies from 165 patients
• 107 males 58 females
• 34 patients followed from time of
  transplantation
• almost all patients had 0PRA

Rodriguez et al AJT 2005 (in press)
6
ROUTINE DIAGNOSTIC PROTOCOL BIOPSIES FROM CARDIAC
TRANSPLANTS
1 mo
2 mo
3 mo
6 mo
1 yr
HE, IP (CD68) FITC (IgG, IgM, IgA, C1q, C4d,
C3d)
7
Number of Patients with Positive Biopsies
17 (10.3)
16 (9.6)
8
(No Transcript)
9
C4d and/or C3d Deposits
(665 consecutive biopsies from 165 patients)
One patient 10 PRA
10
(No Transcript)
11
Incidence of C4d and C3d deposits
Dysfunction n 5
n 4
n 3
C4d
C3d
n 13
C4d C3d
12
Patients with AMR
13
ANTIBODY ASSOCIATED REJECTION
7 years after transplantation anti-DR7 and DRw53
14
Macrophages
15
Response to Therapy
Plasmapheresis and IVIg

• Graft function improved
• DSA decreased or eliminated
• (C consumption not measured)
• C3d deposits cleared first
• Low levels of antibodies (as detected Flow
  beads) can persist beyond C4d

16
Association of Cardiac Allograft
Vasculopathy with C4d C3d and AMR
17
Incidence of C4d and C3d deposits
Dysfunction n 5
n 4
n 3
C4d
C3d
n 13
C4d C3d
18
Second Heart Transplant with Repeat HLA Mismatch
Strong C4d, Little C3d, No HLA antibodies, Good
Function
1st heart HLA-A1
2nd heart HLA-A1
1B
1A
0
12
No antibodies
Class I or II
Baldwin et al 2004 AJT 4311
19
Regulation of Complement Cascade
C3
C5
C6
C2
C4
C7
C1
C8
CD59
C9
C4bp DAF MCP CR1 Factor I
Factor H DAF MCP CR1 Factor I
20
C4d and C3d are Products Complement Regulation
C3
C5
C6
C2
C4
C7
C1
C8
CD59
C9
C4bp DAF MCP CR1 Factor I
Factor H DAF MCP CR1 Factor I
C4d
C3d
21
Sensitization vs Regulation
22
Sensitization vs Regulation
SENSITIZATION
23
Sensitization vs Regulation
C5
C6
C7
C8
C9
SENSITIZATION
24
Epilogue
25
Epilogue
and between different eras in the same center
eg, JHU Increased patients with gt0 PRA 2
patients with episodes of antibody-mediated reject
ion in the first weeks after transplantation
Required longer treatment with PP IVIg
26
Summary
C4d and C3d in Heart Transplants

• Incidence depends on sensitization
• Can occur years after transplantation
• Needs to be correlated with graft function and
  Donor Specific Antibody (DSA) for a diagnosis of
  antibody-mediated rejection
• May be correlated with increased graft
  vasculopathy

27
Clinical studies
E. Rene Rodriguez
Experimental studies
Kenji Minami Kazunuri Murata