overview of transplantation immunology research at the starzl transplantation...
TRANSCRIPT
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Starzl Transplantation Institute &
Departments of Surgery and
Immunology, University of Pittsburgh
School of Medicine
Overview of Transplantation
Immunology Research at the
Starzl Transplantation Institute
for Incoming Students
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“Spare-parts’ surgery, a fantasy for centuries, has progressed
from the impossible to commonplace, prolonging the lives of
patients with end-stage kidney, liver, heart, or lung disease
Transplantation science has also revolutionized basic science,
transcending boundaries between immunology, genetics, cellular and
molecular biology, pharmacology and microbiology
The appeal of transplantation research
Transplantation immunology provides the basis for design of
safer/more effective means to control rejection, alleviate patients’
depedence on anti-rejection drugs and promote transplant tolerance.
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Commonest transplant
“Quality of life ”transplant Live donor transplant
Evolution of transplantation
First successful transplant
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Transplant tolerance can be induced easily in rodents
• Injection of neonatal mice with allogeneic
hematopoietic cells
Billingham, Brent & Medawar, Nature 1953
Many drugs & biologics can induce robust transplant
tolerance
Tolerance occurs rarely in transplant patients (liver and
kidney), but cannot be induced routinely or predicted
But not in humans
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Generation of T cell responses to an organ graft
Halloran PF, NEJM 2004:351;2715
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T cell activation signals serve as targets for
immunosuppressive drugs
Halloran PF, NEJM 2004:351;2715
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Acute rejection is readily controlled but transplant patients suffer
chronic rejection
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Chronic graft rejection
Renal allograft
Heart allograft
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The Current Problem
Immunosuppressive drugs lack
immunologic or Ag specificity
– Increased risk of opportunistic infections and
cancer
– Fail to induce IS drug-free tolerance
• Long-term use of drug therapy results in
non-immunologic side effects
There is clearly an unmet clinical need
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Current goal
• To develop of novel, safe approaches that
will promote sustained, donor-specific
immune hyporesponsiveness, while
lowering the incidence and severity of acute
and chronic rejection and reduce patients’
dependence on anti-rejection drugs
• Is tolerance essential/achievable in
humans?
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What is tolerance?
Specific unresponsiveness to tissue antigens in
the absence of graft pathology and (sustained)
immunosuppressive therapy
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New agents that block costimulation,- a pathway to
tolerance?
Co-stimulatory pathways that might modulate memory T-cell responses in
transplantation and autoimmunity
T cell Antigen-
presenting cell
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New Approaches to Preventing Transplant
Rejection/Promoting Tolerance
Category Therapy
Reducing inflammatory cytokines Anti-IL-6R
Anti-IL-17A mAb
Altering immune cell trafficking CCR5 inhibitor
Inhibition of T and B cell signaling JAK 1/2 inhibitor
B cell depletion Anti-CD20
In vivo Treg expansion mTOR inhibition (+ IL-2)
Cell therapies Tregs
DCregs
MSCs
Inhibition of co-stimulation CTLA4-Ig
Single chain anti-CD28 mAb
Blocking germinal center formation Bcl-6 small molecule inhibitor
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From drugs and biologics to cell therapy:
Treg infusion in transplantation
The new frontier Riley JL, Immunity 2009:30;656
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Important questions regarding regulatory
immune cell (Treg) therapy
The source, number, timing and frequency of cells infused
Choice of immunosuppressive agents
In vivo fate, stability and longevity of the cells
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Immunology Research Topics at
the Starzl Transplantation Institute
stiresearch.health.pitt.edu
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Innate Immunity
• Mechanisms of innate allorecognition
• Role of the innate immune system in acute and
chronic rejection
monocytes
Zhuang Q and Lakkis FG, Kidney Intl 2015:87:712
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Fadi G. Lakkis MD
Innate and adaptive mechanisms of allograft rejection
Oberbarnscheidt, et al, 2014. Non-self recognition by monocytes initiates
allograft rejection. J Clin Invest 124:3579-3589.
Walch et al, 2013. Cognate antigen directs CD8+ T cell migration to
vascularized transplants. J Clin Invest 123:2663-2671.
Walch JM and Lakkis FG,
Curr Opin Organ Transplant 2014:19:28
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Dendritic Cell Immunobiology
How do dendritic cells regulate rejection versus
transplant tolerance ?
Dendritic cells as a potential cellular therapy for
tolerance induction
Raich-regue D, Immunol Letters 2014
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Adrian E. Morelli MD PhD
Dendritic cells, microvesicles, transplant rejection and tolerance
Wang, Z., S. J. Divito, et al, 2012. Dendritic cell therapies in
transplantation revisited: deletion of recipient DCs deters the effect of
therapeutic DCs. Am J Transplant 12:1398-1408.
Montecalvo, A., S. J. Divito, et al, 2012. Mechanism of transfer of
functional microRNAs between mouse dendritic cells via exosomes. Blood
119:756-766.
Robbins PD and Morelli AE Nat Rev Immunol 2014;14:195
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Angus W. Thomson PhD DSc
Roles of dendritic cells and T cells in immune regulation and the
promotion of transplant tolerance
Raich-Regue, D., B. R. Rosborough, A. R. Watson, et al,. 2015. mTORC2 Deficiency
in Myeloid Dendritic Cells Enhances Their Allogeneic Th1 and Th17 Stimulatory Ability
after TLR4 Ligation In Vitro and In Vivo. J Immunol 194:4767-4776. 4417394
Yoshida, O., S. Kimura, B. M. Matta, S. Yokota, et al, 2014. DAP12 deficiency in liver
allografts results in enhanced donor DC migration, augmented effector T cell responses
and abrogation of transplant tolerance. Am J Transplant 14:1791-1805. 4107008
Azimzadeh and Bromberg Nat Rev Nephrol 2013
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Adaptive Immunity and its Regulation
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Geetha Chalasani MD
B cells, alloimmunity and pathogenesis of rejection
Zeng, Q., Y. H. Ng, et al. 2014. B cells mediate chronic allograft rejection
independently of antibody production. J Clin Invest 124:1052-1056.
Ng, Y. H et al 2010. B cells help alloreactive T cells differentiate into
memory T cells. Am J Transplant 10:1970-1980.
Ng Y-H Am J Transplant 2010;10:1970
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Immunological Tolerance
• Innovative strategies to promote tolerance
• Regulatory immune cell therapy
• Mechanisms of transplantation tolerance
• Roles of regulatory immune cells
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David M. Rothstein, MD
Camirand, G., et al.’ 2014. CD45 ligation expands Tregs by promoting
interactions with DCs. J Clin Invest 124:4603-4613.
Yeung, M. Y., Q. Ding, C. R. Brooks, S. Xiao, C. J. Workman, D. A.
Vignali, T. Ueno, R. F. Padera, V. K. Kuchroo, N. Najafian, and D. M.
Rothstein. 2015. TIM-1 signaling is required for maintenance and
induction of regulatory B cells. Am J Transplant 15:942-953.
Regulation of the immune system and tolerance induction
Ding Q and Turnquist HR Cytokine 2013;62:183
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Heth R. Turnquist PhD
Cytokine and dendritic cell immunobiology in transplantation
Reichenbach, D. K et al, 2015. The IL-33/ST2 axis augments effector T-
cell responses during acute GVHD. Blood 125:3183-3192.
Matta, B. M., B. R. Rosborough et al,. 2014. IL-33 is an unconventional
Alarmin that stimulates IL-2 secretion by dendritic cells to selectively
expand IL-33R/ST2+ regulatory T cells. J Immunol 193:4010-4020.
Liu Q and Turnquist HR Cytokine 2013;62:183
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Liver transplant research in the lab and clinic
Immunosuppression can be safely withdrawn in about 20%
of stable transplant patients
Livers are accepted across MHC barriers without
immunosuppression in mice
Tolerogenic function of liver APCs?
Role of Tregs?
Intrahepatic T cell apoptosis?
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Human Transplant Immunology
• Immunological monitoring of the transplant recipient
• Mechanisms of rejection in humans
• Mechanisms of graft acceptance (tolerance) in
humans
• Immunogenetics
• Viral infections in transplantation
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Diana M. Metes MD
Human immunology, transplantation, EBV, T cell memory, dendritic cells
Macedo, C et al,. 2011. EBV-specific CD8+ T cells from asymptomatic
pediatric thoracic transplant patients carrying chronic high EBV loads
display contrasting features: activated phenotype and exhausted function. J
Immunol 186:5854-5862.
Wiesmayr, S.et al, 2012. Decreased NKp46 and NKG2D and elevated
PD-1 are associated with altered NK-cell function in pediatric transplant
patients with PTLD. Eur J Immunol 42:541-550.
Memory T Cells in Alloimmunity
Macedo C Am J Transplant 2009;9:2057-66
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Xenotransplantation
• Identification of novel xeno-antigens
• Humoral and cellular mechanisms of
xenograft rejection
• Genetic engineering of (donor) pigs for
xenotransplantation
• Pre-clinical, non-human primate studies
(heart, kidney and pancreatic islets)
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David K.C. Cooper MD PhD
Iwase, H. et al, 2015. Pig kidney graft survival in a baboon for 136 days:
longest life-supporting organ graft survival to date. Xenotransplantation
22:302-309.
Bottino R et al, 2014. Pig-to-monkey islet xenotransplantation using multi-
transgenic pigs. Am J Transplant 14:2275-2287.
The potential of cross-species organ transplantation (xenotransplantation)
Cowan PJ Kidney Int 2014;85:265
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Recent Graduate Student Trainees
in Transplantation Immunology
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Sherri Devito, MD PhD
NIH Training Fellowship
Thesis: The role of tolerogenic dendritic cells in islet-cell
allograft transplantation
Now: Harvard University/MGH
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Ben Matta, PhD
NIH Training Fellowships
Thesis: Regulation of T cell function by liver plasmacytoid
dendritic cells
Now: Postdoctoral Research Fellowship, STI (Turnquist
Lab) AST Fellowship
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Dawn Reichenbach, PhD
NIH Training Fellowship
Thesis: Effects of Local Graft Inflammation on the Innate
and Adaptive Immune Response to Solid Organ
Transplantation
Now: Postdoctoral Fellow, Blazar Lab, University of
Minnesota
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Brian Rosborough, MD PhD
AHA and NIH Training Fellowships
Thesis: Regulation of alloimmunity by mTOR inhibition
Now: Harvard University/MGH
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Jeff Walch, MD PhD
Principal Mentor: NIH Training Fellowship
Thesis: Migration of T cells to vascularized allografts
Now: Johns Hopkins University School of Medicine
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NIH T32 fellowships
Interdisciplinary Training in
Transplantation Biology
A unique, NIH-supported interdisciplinary training program in
transplantation biology to train future leaders in transplantation
research. Training positions for pre-doctoral graduate students (PhD
or MD/PhD candidates) and for post-doctoral fellows (PhDs, MDs,
MD/PhDs and VDMs) are available. Candidates for support from the
institutional NIH T32 training grant must be US citizens or permanent
residents