Transplantation Immunology

Lucian P. Jiga, MD, PhD

3rd century, AD

9th century, AD

1818 - 1st successful blood transfusion

1831 - Frankenstein published

1st documentation for use ............................... of cadaver parts/organs

20th century - Tx becomes reality

Eduard K. Zirm - 1905 - 1st cornea Tx

A. Carrel - 1902-1908 - vascular suture

P. Medawar & FM. Burnet - 1940 - acquired immune tolerance

Acquired immunity
Strain B - Recipient 10 days ADAPTIVITY Acute rejection - 1set kinetics Strain B - Recipient 3 days Hyperacute rejection - 2 set kinetics MEMORY

Strain A - Donor

Strain B - Recipient 3 days Hyperacute rejection - 2 set kinetics LYMPHOCYTES

10 days Acute rejection - 1set kinetics Strain C - Donor

SPECIFICITY

Immunological tolerance

Immunological tolerance
SKIN GRAFT

Immunological tolerance
SKIN GRAFT

ACCEPTANCE

Immunological tolerance
SKIN GRAFT

ACCEPTANCE

SKIN GRAFT

Immunological tolerance
SKIN GRAFT

ACCEPTANCE

SKIN GRAFT

REJECTION

Immunological tolerance
SKIN GRAFT

ACCEPTANCE

SKIN GRAFT

REJECTION

CELL PRECONDITIONING

Immunological tolerance
SKIN GRAFT

ACCEPTANCE

SKIN GRAFT

REJECTION

SKIN GRAFT

CELL PRECONDITIONING

Immunological tolerance
SKIN GRAFT

ACCEPTANCE

SKIN GRAFT

REJECTION

SKIN GRAFT

ACCEPTANCE
CELL PRECONDITIONING

1954 -1st kidney transplant

...the rest is history

T. Starzl - 1967

C. Barnard - 1967 J. Hardy - 1963

AZA & CyA - 1962 - 1970 (1983 - FDA approved)

...the rest is history

1984 - Baby Fae receives a baboon heart 1992 - 1st baboon to human liver Tx 1993 - 2nd baboon to human liver Tx

...the rest is history

1998 - 1st hand transplant

2005 - 1st part-face Tx

2011 - 1st full-face Tx in USA

...so what happens after Tx In the absence of immunosuppression 1. Alloantigen recognition 2. T-cell activation 3. Allograft destruction

ACUTE REJECTION

Alloantigen recognition
Tx between the same inbred strain will never be rejected Tx between individuals of different inbred strains will almost always be rejected Offspring of 2 different inbred strains (F1 hybrid) will never reject grafts from either parents an F1-derived graft will almost always be rejected by either parents

polymorphic codominantly expressed molecules ................are responsible for rejection

Polymorphism = graft antigens differ among individuals/species Codominance = (AxB)F1 accepts A-B parental grafts Codominance = A or B parents will reject (AxB)F1 grafts

Alloantigen recognition
MHC molecules are responsible for acute rejection after Tx

Alloantigen recognition
MHC molecules are responsible for acute rejection after Tx

Graft-inltrating APCs

Alloantigen recognition
MHC molecules are responsible for acute rejection after Tx

Graft-inltrating APCs

Recipient APCs

Alloreactive T cell activation

http://www-ermm.cbcu.cam.ac.uk

remember MHC & Antigen processing course!!

types of rejection

types of rejection

types of rejection

The fate of allografts

www.ctstransplant.org

The fate of allografts

n = 131985

www.ctstransplant.org

The fate of allografts

n = 131985

www.ctstransplant.org

The fate of allografts

n = 131985

www.ctstransplant.org

The fate of allografts

www.ctstransplant.org

The fate of allografts

www.ctstransplant.org

The fate of allografts

www.ctstransplant.org

The fate of allografts

www.ctstransplant.org

The fate of allografts

www.ctstransplant.org

The fate of allografts

www.ctstransplant.org

Ways to avoid/treat rejection

Immunosuppression
Non-specic dreadful side-effects (PTLD, infections) cannot overcome chronic rejection Cyclosporine A FK-506 MMF Rapamycin Corticosteroids ATG

Tolerance
Antigen-specic no side-effects absent chronic rejection

Holy grail

Ways to induce tolerance

Janeway CA et al - Immunobiology, 5th edition

CD80/86 (B7.1/ B7.2)

CD28

Ways to induce tolerance

Janeway CA et al - Immunobiology, 5th edition

Transgenic IDO, TGFb, IL10, CTLA4, PD-1 VDR/1.25-(OH)(2)D3

CD80/86 (B7.1/ B7.2)

Immature DCs Selective OGN

CD28

Ways to induce tolerance

Janeway CA et al - Immunobiology, 5th edition

Transgenic IDO, TGFb, IL10, CTLA4, PD-1 VDR/1.25-(OH)(2)D3

CD80/86 (B7.1/ B7.2)

Immature DCs Selective OGN

TRP depletion HAA, Ky, 3-OH-Ky

CD28

costim. blockade FoxP3 Tregs

Ways to induce tolerance

Janeway CA et al - Immunobiology, 5th edition

Transgenic IDO, TGFb, IL10, CTLA4, PD-1 VDR/1.25-(OH)(2)D3

CD80/86 (B7.1/ B7.2)

Immature DCs Selective OGN

TRP depletion HAA, Ky, 3-OH-Ky

CD28

costim. blockade FoxP3 Tregs

Ways to induce tolerance

Janeway CA et al - Immunobiology, 5th edition

Transgenic IDO, TGFb, IL10, CTLA4, PD-1 VDR/1.25-(OH)(2)D3

CD80/86 (B7.1/ B7.2)

Immature DCs Selective OGN

TRP depletion HAA, Ky, 3-OH-Ky

CD28

costim. blockade FoxP3 Tregs

T cell anergy

The future............

In-vitro organ manufacturing

Xenotransplantation - GT-knockout pig

http://www.youtube.com/watch?v=ibtXFG2c42A