K30 Research Update

Sherilyn A Gordon M.D.

December 20, 2006

Transplant Immunomodulation by

Allochimeric Molecules

Background-Transplant-Related

Morbidity and Mortality

Technical Expertise

Perioperative care

Immunoprophylaxis Complications

infection

rejection

Increasing Demand for Organs

www.unos.org

5000

10,000

0

88 89 90 91 92 93 94 95 96 97 98 99 00

Waiting List 15 fold increase

Donors 2.4 fold increase

Deaths 5 fold increase

Transplants 2.4 fold increase15,000

20,000

Effect of HLA Matching on Renal Allograft Survival

P. P. TerasakiTerasaki

Background

Antigenic Topography of Class I Molecules

1 2 3

1 50 90 180

270

dominant immunogenic

epitopes

RT1.Aa, RT1.Au, RT1.Al

1. accelerated allograft

rejection

2. alloantibody production

3. increase fTc

Background

Rat Major Histocompatibility Complex

A Pa F B D E

II

90 182

TM CYT1

1a 2 a 3

I I

RT1.A a

RT1

Background

Allochimeric Class I MHC MoleculesAllochimeric Class I MHC Molecules

1 182

N a 3 a

TM CYT

91

2 domain

1 a

[ 2 ]-RT1.Aa

51 901 182

N a

1 Helix

2 a

3 a

TM CYT

[ 1 ]-RT1.Aa

901 182

2 a

3 a

TM CYT

[N4] -RT1.A a

N a

901 182

2 a

3 a

TM CYT

1

a

Background

ACI (RT1.Aa)

LEW (RT1.Al)

or

WF (RT1.Au)

1mg / p. v.

Chimeric Alloantigen

a au/l

orally

CsA

3 days (0-2)

10mg/kg

Experimental Tolerance Model

0

20

40

60

80

100

0 20 40 60 80 100

Days

WF ACI

WF ACI CsA only

WF ACI + 1hu/l-RT1.Aa +

CsA

Long-Term Survival of WF Allografts Induced

by Perioperative Allochimeric Administration

% g

raft

su

rviv

al

Preliminary Data

0

20

40

60

80

100

0 20 40 60 80 100

Days

% g

raft

su

rviv

al

LEW ACI

LEW ACI CsA only

LEW ACI + 1hu/l-RT1.Aa +

CsA

Long-term Survival of LEW Allografts

Induced by Allochimeric Molecule

Preliminary Data

Rejected

third-party

allograft

Accepted

donor-type

allograft

Tolerance Induction by Allochimeric Molecules

Preliminary Data

SYNGENEICALLOCHIMERIC

PROTEIN

H&E

EVG

TRI

DAY 120 CsA High Dose

Islet

Donor

Recipie

nt

CsA [ 1hl/u]-

RT1.Aa

Survival

(days)

MST + SD

WF ACI - - 10 x 2, 13 11 + 1.7

WF ACI + - 6, 13 9.5 + 4.9

WF ACI - + 16, > 90 -

WF ACI + + >96, >98, >200 x 3 > 100

LEW ACI + - 15, 19 17 + 2.8

LEW ACI - + 7, 9, 17, 20 13.25 + 6.2

LEW ACI + + 14, 21, >47, >89, >

100 x 2

> 100

Preliminary Results In Islet Transplantation

Preliminary Data

Proposal

SSpecific Aim I•To document the induction of tolerance to pancreatic

islets by allochimeric molecules

Hypothesis: Rat allochimeric molecules induce

tolerance to islet allografts in allogeneic hosts

Proposal

SSpecific Aim II•To dissect the mechanisms of tolerance induction by

allochimeric molecules

Hypothesis: Regulatory T cells that are critical for

tolerance acquisition can transfer the tolerant state to

naïve recipients in an “infectious” manner

-Determine the contribution of distinct cytokine

networks

-Determine the role of T Cell anergy

ProposalSSpecific Aim III

•To further determine sites of amino acids that are

critical for tolerance induction

Hypothesis: Allochimeric determinants, that are

critical for tolerance indcution, are located on the

polymorphic regions of class I MHC molecules

Translation to Clinic

•IRB

•Timing of pre-transplant treatment regimen

•Sesitivity of indicators of tolerance

•Graft survival

•Freedom from rejection

•Donor-specific antibodies

•R. Mark Ghobrial, M.D., Ph.D. (Lead Mentor)

•Ronald W. Busuttil, M.D., Ph.D.

•Curtis Holt, Pharm.D.

•XD Chen, Ph.D.

•F Gao, Ph.D.

Acknowledgments