Introduction to Liver Transplant Immunology
Jaeseok Yang, M.D., Ph.D. Transplantation Center, Seoul National University Hospital
Transplantation Research Institute, Seoul National University
Immunity vs. Tolerance
Self
Nonself Immunity
Tolerance
PRR TCR
Thymic negative selection
Regulation
Antibody
Self or Nonself ?
Tolerance vs. Accommodation vs. Rejection
• Rejection − Spontaneous immune response to allograft
• Accommodation – No harmful immune attack despite the presence of antibodies
• Tolerance – Absense of donor-reactive immune cells and antibodies
• Induction of donor-specific tolerance – Acceptance of allograft – Without further immunosuppression – With intact immune response to other foreign antigens
From Alloantigen Recognition to Graft Destruction
Secondary lymphoid organs
Antigen presentation
Migration of donor-derived and recipient-derived dendritic cells
Migration of activated T cells and antibodies
B
T Activated
T cells
Memory B cells and plasma cells
Tissue destruction
T
B
Resolution
T cell Activation
Effector Phase
Step I : Antigen Presentation in TPL
Direct presentation Indirect presentation
Semidirect presentation
Importance of MHC (HLA)
• MHC-restriction – T cells recognize self MHC plus foreign peptide, not
peptide alone – T cell receptor reacts with one antigen in combination
with one MHC molecule
Mechanisms of Direct Allorecognition
• Allorecognition of donor as an altered self – Recipient MHC-restricted TCRs recognize (donor MHC + donor peptides) as (recipient MHC + donor peptides)
• High alloreactive precursor frequency – Up to 2% of T cells vs. peptide specific T cells (1/105~1/106)
Revised from Cellular and Molecular Immunology, 5th edition
Dendritic Cells As a Professional APC
• ‘Sentinel’ to detect signs of ‘danger’ or ‘nonself’ – Pattern recognition receptor : induce the maturation of DC
• Upregulate MHC, costimulatory molecules (CD80, CD86, CD40) • Induce of chemokine receptors (CCR7) • Secrete cytokines (IL-6, IL-12, TNF-α, type I interferon)
• ‘Messenger’ to induce cellular activation
Donor Tolerogenic DC in Transplantation
T Cells Play A Key Role in Rejection
T deficient
T cells
T deficient
Step II : T Cell Activation in TPL 2 signal model : Signal 1 + 2 (positive vs. negative)
Bishop GA et al. Transplantation
2011; 91: 1065-1074
JAK-3 Inhibitor
FK778 de novo pyrimidine synthesis
T Cell Growth Factors : Signal 3
Migration : dhesion molecules & chemokines
Step III : Effector Phase of Alloimmunity
Humoral Immune Response
• Hyperacute rejection : preformed anti-donor antibody • Acute antibody-mediated rejection
– Newly formed, T cell-dependent anti-donor antibody
• Chronic antibody-mediated rejection : chronic vascular damages
Humoral Immune Response
Activation of Complement pathway
Complement- dependent tissue injury
Plasmapheresis IVIg
Splenectomy Anti-CD20 IVIg
B cell
Helper T cell
Memory B cell
Plasma cell
ATG IL-2Ab FK506 MMF
Splenectomy Bortezomib IVIg
C5 Inhibitor
Complement- independent tissue injury
B-Cell/Humoral Immunity Targeting Therapy
Innate Immune Responses
• Pattern recognition receptors : toll-like receptors – Endogeneous ligands : ischemia-reperfusion injury – Exogeneous ligands : opportunistic infection – Toll-like receptors – Contribute the rejection and interfere with tolerance
• ‘Metastable tolerance’
• Humoral effectors : complements – Classic pathway : C4d deposition in humoral rejection – Local C3 production : costimulation for APC-T interaction
Sachs SH, Nat Med, 2002
– Role of DAF & alternative pathway in APC-T interaction Heeger PS, Medof ME, JEM, 2007
Interaction between Innate & Adaptive Immunity
• Cellular effectors – Neither sufficient nor necessary – Neutrophil & macrophage : earlier infiltration to grafts – NK cells : role in rejection in CD28-/- recipients Pfeffer K, Nat Med, 2001
• Two main roles of innate immunity in rejection – Efficient antigen presentation to T cells – Effector functions under the lead of adaptive immunity (T cells)
• Phagocytosis, killing; ROS; cytokines or chemokines
Classification of Rejection of Transplantation
• Hyperacute : a preformed-antibody mediated response • Acute T-cell mediated rejection • Chronic – multifactorial
– immune factors – nonimmune factors
0 1 6 12 24 Post-TPL time (months)
Rel
ativ
e R
isk
hyperacute acute chronic
Step IV : Resolution of Immunity in TPL
• Resolution of allograft rejection – Apoptosis of donor-reactive T & B cells - Generation of memory T & B cells/preformed antibodies
• Accelerated rejection – Retransplantation with the sensitized alloantigens
Accelerated Rejection in Second-set TPL
Regulatory Cell Population
• Naturally occuring Tregs vs. adaptive (induced) Tregs • CD4+ T cells
– CD4+CD25+ Tregs, CD103+ Tregs, CD4+CD25- Tregs – Tr1 cells: Ag-induced, IL-10+, ROG+, Granzyme A+, Foxp3- – Th3 cells : TGF-β production, Foxp3+
• CD8+ T cells – CD8+ Tregs : Qa-1 (HLA-E) restricted Treg for CD4+ T cell – IL-10 producing CD8+CCR7+ or CD8+CD122+Foxp3- Tregs – CD8+CD28-Foxp3+ T cells (human), CD8+CD25+Foxp3+
• CD4-CD8- T cells : cytotoxicity toward T cells • γδT cells • Regulatory B cells
– CD19+, CD1d+, IL-10+, CD5+, TIM-1+
Regulatory T Cells in Transplantation
• Concept of linked suppression and infectious suppression
Tolerance Dynamic Balance Between Effectors T Cells & Tregs
Rejection Tolerance Rejection Tolerance
• Deletion – Reduce the clone size of alloreactive T cells
• Regulation – A key role in maintain a tolerance – Expansion of naïve Tregs or induction of adaptive Tregs
Tregs
Effector T cells
Induction & Maintenance of TPL Tolerance
Why Is Transplant Tolerance Hard to Achieve? Why Is Rejection the Strongest Immune Reaction?
• Very high frequency of alloreacitve T cells • Influence of innate immune response
– Weak rejection in small animal models in SPF conditions – Difficult tolerance induction in outbreed animal, non-
human primates and clinical settings
• Existence of memory T cells – Prior direct alloantigen exposure : prior transplantation,
transfusion, pregnancy – Heterologous immunity – Homeostatic proliferation
Mechanisms of Weaker Rejection in Liver TPL
• Production of donor-strain soluble MHC I by liver • Soluble HLA-G in LT and SLK inhibits T, NK, and DCs. Transplant Immunology Volume 17, Issue 2, 98–107 • Donor-derived microchimerism by passenger stem cells • Mass effects, AICD, IDO etc.
Orlando G et al, J Hepatol 2009;50:1247-1257
• Endotoxin tolerance: dendritic cells, kupffer cells, sinusoidal endothelial cells, and hepatocytes lead to tolerization of T cells – Tolerance can be reversed by infection
• Innate immunity such as NK and NKT cells – Anti-HCV specific T cells do not induce rejection Gastroenterology. 2011 Jan;140(1):51-64
Clinical Operational Tolerance in Liver TPL Tolerance development in 20% of liver TPL
Remove immunosuppressants in nonimmunologic original liver disease Rejection can be reversed by steroid pulse therapy Liver damage can be repaired easily by regeneration