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

“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.

Commonest transplant

“Quality of life ”transplant Live donor transplant

Evolution of transplantation

First successful transplant

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

Generation of T cell responses to an organ graft

Halloran PF, NEJM 2004:351;2715

T cell activation signals serve as targets for

immunosuppressive drugs

Halloran PF, NEJM 2004:351;2715

Acute rejection is readily controlled but transplant patients suffer

chronic rejection

Chronic graft rejection

Renal allograft

Heart allograft

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

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?

What is tolerance?

Specific unresponsiveness to tissue antigens in

the absence of graft pathology and (sustained)

immunosuppressive therapy

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

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

From drugs and biologics to cell therapy:

Treg infusion in transplantation

The new frontier Riley JL, Immunity 2009:30;656

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

Immunology Research Topics at

the Starzl Transplantation Institute

stiresearch.health.pitt.edu

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

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

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

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

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

Adaptive Immunity and its Regulation

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

Immunological Tolerance

• Innovative strategies to promote tolerance

• Regulatory immune cell therapy

• Mechanisms of transplantation tolerance

• Roles of regulatory immune cells

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

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

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?

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

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

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)

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

Recent Graduate Student Trainees

in Transplantation Immunology

Sherri Devito, MD PhD

NIH Training Fellowship

Thesis: The role of tolerogenic dendritic cells in islet-cell

allograft transplantation

Now: Harvard University/MGH

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

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

Brian Rosborough, MD PhD

AHA and NIH Training Fellowships

Thesis: Regulation of alloimmunity by mTOR inhibition

Now: Harvard University/MGH

Jeff Walch, MD PhD

Principal Mentor: NIH Training Fellowship

Thesis: Migration of T cells to vascularized allografts

Now: Johns Hopkins University School of Medicine

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