8. Transplants and the immune
system
Immune response against transplants
depends on the presence in the grafted
tissue of antigens that are absent in
recipient and hence recognized as
10. Antibodies are induced by microbial antigens, but cross react with polysaccharide
antigens found on red blood cells.
Individual will not produce antibodies that react with own RBC (self-tolerance).
The blood type of an individual can be determined by an agglutination assay: look
for ability of serum to bind to, and agglutinate RBC from another individual.
11. Transplantation antigens
Major Histocompatibility Complex (MHC):
(主要組織相容複合體)
– gene complex whose alleles encode
polymorphic cell surface glycoproteins
involved in antigen recognition and presentation
– nomenclature
• HLA: human leukocyte antigen
• SLA: porcine leukocyte antigen
• H-2: mouse MHC
• RT1: rat MHC
17. The basic antibody is a dimer
of dimer (2 heavy chain-light
chain pairs)
composed of repeats
of a single structural
unit known as the
“immunoglobulin
domain”
22. Antibody Mediated Rejection
• AMR
Graft rejection caused by Ab directed against HLA
molecules, ABO antigens or endothelial cell
antigens
• Clinical Rejection
Biopsy confirmed with associated graft dysfunction
• Subclinical Rejection
Histological changes specific for acute rejection on
protocol biopsy w/o graft dysfunction
23. Definitions
• Hyperacute Rejection
– Due to preformed Ab
• Early AMR
– Due to Ab response
• Late AMR
– Due to de novo Ab production
• Chronic AMR
– Recall secondary Ab response
• Mixed rejection
• Accomodation
– Resistance to injury in
presence of Ab
24.
25. Donor/Recipient Matching
• Three factors are involved in tissue
matching and antibody production
– Human leukocyte antigen (HLA) typing
– Crossmatch
– Panel-reactive antibody (PRA)
26. HLA Matching
• Three groups of HLA proteins:
– HLA-A
– HLA-B
– HLA-DR
• One HLA in each group (haplotype) is inherited from each
parent
Example:
Mother = A1, A2, B8, B44, DR3,4
Father = A3, A10, B7, B55, DR11,15
Child = A2, A10, B7, B44, DR4,15
27. Crossmatch
• Crossmatch tests whether the recipient has
antibodies to the potential donor
– Negative crossmatch is desired
– Positive crossmatch increases risk of rejection
– Antibodies can develop, so repeat crossmatch
testing is required immediately before transplant
28. Panel-Reactive Antibody (PRA)
• PRA is the amount of HLA antibody present in the
recipient’s serum (expressed as a percentage)
– Determined by testing the recipient’s serum against a
panel of cells from 60 people with different HLA proteins
– HLA antibodies can change, especially in response to
blood transfusion, prior transplant, or pregnancy
– Higher % PRA makes finding a donor more difficult
36. DSA + at Transplant
“Preformed DSA”
DSA - at Transplant
≥35%
Acute Antibody
Mediated Rejection
Dunn et al. Am J Transplant 2011;11:2132
Up to 15%
1- year Graft Failure
Rate (non-desensitized)
Lefacheur et al. Am J Transplant 2008;8:324
37. DSA + at Transplant
“Preformed DSA”
DSA - at Transplant
<5%
Acute Antibody
Mediated Rejection
Dunn et al. Am J Transplant 2011;11:2132
De novo anti-HLA
DSA in the first year
And beyond
Everly et al. Am J Transplant 2012; In submission
Smith et al. Am J Transplant 2011;11:312
39. Major concern with preformed DSA,
sensitized patient, is the associated AMR
Risk.
In the past, transplantation is
contraindicated!
Today, can we change
this situation?
42. ABOi liver transplant
• ABO blood type incompatible liver Tx
• Since 2012 in Taipei-VGH
• All LDLT
• 13 cases (11 adult and 2 pediatric)
• Graft type: 10 RL, 1 LL, 2 LLS
• One mortality but not ABOi related
• No ABOi related acute rejection/
complications
43. Protocol of Preoperative Preparation
• Rituximab (375 mg/mm2 body surface area)
– once at 2 weeks before transplantion
• Plasma exchange (PE) / double filtration Plasmaphresis (PP)
– the frequency and timing of PE depends
– the level of hemagglutinin (HA) titer, aiming at a titer of 1:64 or
less before OLT
• No induction regimen
• Immunosuppression
– Intravenous methyprednisolone (10 mg/kg) administered before
reperfusion
– Maintenance: methylprednisolone, tacrolimus, mycophenolate
mofetil
• Post Tx monitoring
44. Rituximab : Suppression/Depletion of B-cells
• Genetically engineered chimeric MoAb w/ mouse fused with
human IgG
• Indication:
– FDA approved for Non-hodgkin’s Lymphoma, rheumatoid arthritis.
• Action:
– binds to the CD20 antigen
– located on pre-B & mature B lymphocytes: mediates B cell lysis
– No effect on plasma cells
• Adverse effects:
– hypersensitivity reactions
– Cytopenias
– Fever
– infection risk
• Dose
– 375 mg/m2 BSA IV
Singh et al, Transplantation Review, 2009
Micromedex
45. PP/PE : Elimination of Circulating Ab
• Eliminating DSA effectively
• Used in combination with other therapies
• Adverse effects:
– Nonselective removal of proteins, coagulation
factors, albumin, Abs…
– Coagulopathy
– Problems of fluid balance
• Decision to stop PP/PE should be based on:
– elimination of donor-directed HLA antibody
– establishment of good graft function
– confirmed by Bx
Singh et al, Transplantation Review, 2009
Apheresis Guidelines, 2009
46. Sensitized patient treatment
• 陳小姐, 36 Y/O
• SLE, lupus nephritis, ESRD
– 2007-6 PD, infection
– 2009-7 HD
– 2009-9, on waiting list
• High PRA level: 2009-12, Class I/II: 97/99%
• HLA typing: A11, 33; B58,39; CW3,7; DQ2,6
54. Prognosis of AMR
• Vasculopathy
• Fibrosis
• Loss of graft
function/graft
loss
Devries, 2003, Sem in Imm 15:33-48
55. AMR Treatment
• Suppression of T cell response
• Suppression/Depletion of B cells
• Elimination of circulating Ab
• Inhibition of Ab
• Depletion of plasma cells
• Complement inhibition
56. 56
Tempo of rejection reaction
chronic
type of
rejection
accelerated
hyperacute
acute
months-years
time taken
minutes- hours
days
days-weeks
unclear causes: cross reactive Ab,
immune complexes, slow cellular
reaction, tolerance breakdown,
disease recurrence
cause
preformed anti-donor
antibodies and complement
reactivation of sensitized T cells
(secondary response)
primary activation of T cells
57. Suppression of T-cell Response
Depletional Antilymphocyte Ab (rATG)
• Has multiple anti-T cell Ab specificities, costimulatory pathways, cell
adhesion molecules, cell surface molecules expressed on B cells and
plasma cells.
• Usually used as adjuvant therapy in AMR
• Used for severe or steroid resistant ACR
• FDA approved for Kidney transplant rejection
Steroids
• inhibits IL-1,IL-2, IL-6 production, T-cell proliferation, cytokine gene
transcription & antigen presentation
CNI
• Both CsA & Tac inhibit T & B-cell activation and proliferation
• FDA approved for kidney, liver, heart
Singh et al, Transplantation Review, 2009
Samaniego et al, Nature Clinical Practice, 2006
micromedex
58. 抗排斥藥物
• Treatment of T-
lymphocyte-
mediated rejection
• Multipoint targeting
of the interleukin-2
pathway
• Partially effective in
antibody-mediated
rejection (AMR)
60. Nickeleit, Neph Dial and Transplant 18: 2232-2239, 2003
Peritubular capillary
Immunofluorescent
Staining
for C4d
Peritubular capillary
Immunohistochemistry
staining
for C4d.
61. AMR Treatment
• Suppression of T cell response
• Suppression/Depletion of B cells
• Elimination of circulating Ab
• Inhibition of Ab
• Depletion of plasma cells
• Complement inhibition
62. AMR Treatment
• Suppression of T cell response
• Suppression/Depletion of B cells
• Elimination of circulating Ab
• Inhibition of Ab
• Depletion of plasma cells
• Complement inhibition
63. AMR Treatment
• Suppression of T cell response
• Suppression/Depletion of B cells
• Elimination of circulating Ab
• Inhibition of Ab
• Depletion of plasma cells
• Complement inhibition
64. Inhibition of Antibody
Immune Globulin (IVIG)
Highly purified human IgG
• Action:
• immunomodulatory effects
• Down regulates antibody
• T & B cell suppression
• Adverse effects:
• Allergy
• AKI
• Arthralgias, mylagias, HTN, hypotension, MI
– T ½ = 3 weeks
– Range 100 mg/kg to 2 gm/kg
66. 1/12 1/19
2/21 3/5
Case sharing
•47y/o, male, uremia
with unknown cause,
under HD for 5yrs
•2013-9-29 DDKT, acute
rejection, and 4
combined
immunosuppressant
• 2014-1-12 acute
cholecystitis s/p PTGBD,
s/p OC
• Progressed to
necrotizing pancreatitis,
s/p CT guided drainage,
s/p retroperitoneal
debridement for twice
• Profound sepsis, s/p
IVIG (1g/kg) for three
times ($50,000NTD)
• Saved the life
67. AMR Treatment
• Suppression of T cell response
• Suppression/Depletion of B cells
• Elimination of circulating Ab
• Inhibition of Ab
• Depletion of plasma cells
• Complement inhibition
68. Bortezomib
Depletion of Plasma cell
• Reversible proteasome
inhibitor
• Indication: FDA
approved for multiple
myeloma.
• Dose: 1.3 to 1.5 mg/m2
IV day 1, 4, 8, 11.
• Adverse effects:
– Neuropathy
– plt
– WBC
– GI symptoms
Everly et al, Transplantation, 2008
Djamali et al, Clinical Transplants, 2009
Sollinger et al, WTC Abstract 2010
Delete the out-of-control
Ab production
69.
70. AMR Treatment
• Suppression of T cell response
• Suppression/Depletion of B cells
• Elimination of circulating Ab
• Inhibition of Ab
• Depletion of plasma cells
• Complement inhibition
73. Monitoring during treatment
• Graft function
• Infection
– Viral, bacterial, fungal
• Bone marrow
suppression
– Leukopenia,
thrombocytopenia,
anemia
• DSA
• Immunosuppression
• Repeat biopsy
74. PREVENTION
• DAWN
• Drug Administration With Necessity
•Identify who is at risk
• Sensitized
• Crossmatch (+)
• Certain disease states (SLE, PSC)
• Monitor
• DSAs, Biopsy, organ function
75. Chimera – The God of War
• Chimerism
• Tolerance
• The ultimate goals for transplantation
76. The most influential people in modern organ transplantation
Thomas E. Starzl
Paul Ichiro Terasaki
