Transplantation Immunology 1

Transplantation: Chapter 17

You are not responsible for:Immunosuppressive therapiesClinical aspects of specific organ transplants

TransplantsOrgan in 2005Cornea 47,000Kidney 16,477Liver 6444Heart 2127Lung 1408Pancreas 570

Self-Test Questions:Intro: allA.I: 1 – 5, 7, 8A.II: 2 – 4B: 2, 3, 5C: 1D: 4E: 2

Transplantation Immunology 2

What are different types of tissue transplants?

Sources-- Living donor; & self-- Cadaver-- Animal

Autologous graft-- e.g., skin, artery transplants-- not rejected

Isograft -- e.g., any organ-- not rejected

Allograft-- kidney, liver, heart transplants-- rejected; unless Im privileged

Xenograft-- rejected, unless non-antigenic-- e.g., heart valves

Transplantation Immunology 3

What are types of rejection?

1. Host-vs-GraftHyperacute rejection

-- rapid: minutes to hours-- humoral; existing Abs; complement

-- blood type-- xenografts

Acute rejection -- humoral or cell mediated-- days/weeks

Chronic rejection-- months / years-- despite immunosuppressive therapy

Long term not much improved-- Kidney: half-life only 8-10 years

2. Graft-vs-Host (discussed later)

Recipient Abs against donor MHC

Recipient CTLs attackdonor cells

Recipient Abs, attack donor cells

5 Year survival rate (2009)Kidney: 69.3%Heart: 74.9%Liver: 73.8%Lung: 54.4%

Transplantation Immunology 4

What are the mechanisms of Immune rejection

Direct vs Indirect allo-recognition

Effector cells

Rejection mechanisms

Transplantation Immunology 5

What causes ‘Direct’ allo-recognition?

Primary mechanism of rejection(10x greater than indirect)

Recipient T-cells are activated by: Graft-MHC + Graft peptides

Why would T-cells bind to peptides in non-self MHC? Graft-MHC + peptide can resemble … Self-MHC + foreign peptide

May contribute mostly toward acute rejection

MHC + peptide

Transplantation Immunology 6

What causes ‘Indirect’ allo-recognition?

Recipient T-cells are activated by recipient MHC + graft (MHC) peptides

Analogous to normal T-cell response to pathogens (or vaccines)

Recipient DCs migrate into graft and phagocytose Ags

-- fewer T-cells respond (most AG being ‘self’) but among these will also be…-- MHC peptides -- Minor Histocompatibility Antigens

May contribute mostly toward chronic rejection

-- graft DCs soon removed from body

Transplantation Immunology 7

When does Graft vs Host Disease (GvHD) occur? -- bone marrow -- some solid organ

Immune cells of graftreact against recipient tissues -- Allo-reactive antibodies -- Cell-mediated attack

Occurs in 75%+ of bone marrow transplants

But has beneficial effect against leukemic and cancerous cells

Transplantation Immunology 8

What are the primary anti-rejection therapies?

1. Corticosteroids, e.g., prednisone

2. Anti-proliferatives, e.g., azothrioprine

3. T-cell signaling/activation disruptors a) chemotherapeutic agents

-- IL-2 inhibitors; e.g., cyclosporine-A, rapamycin

b) humanized Mabs -- anti-CD3 -- anti-IL2r (e.g., basiliximab) -- anti-CD20, a B-cell AG) (e.g., rituximab)

c) fusion molecules -- B7 antagonist (blocks B7/CD28 interaction)

-- e.g., Belatacept; CTL-4 + IgG FC

Cyclosprine-A

Transplantation Immunology 9

Organ perfusion prior to transplant can minimize direct acute rejection

-- why?-- also improves organ performance

What are some experimental anti-rejection therapies?

1. Bone marrow HSC transplants-- transplant HSC from done to recipient

2. Thymic manipulation-- inject donor AG into recipient thymus

3. Treg cell induction-- in vitro or in vivo

4. and others…

Transplantation Immunology 10

How is tissue-matching performed? -- minimizes HLA incompatibility

1. Alloantibody Screening-- Abs against specific HLA

2. HLA (tissue) matching a) Serological

-- use HLA specific mABs

b) DNA analysis-- look for HLA-allele specific sequences

Not all HLA tested for… Why?

HLA typing at NY Blood Center Serology HLA Class I (A,B,C) HLA Class I HLA-B27

DNA analysis PCR- broad allele class resolutionHLA Class I (A,B,C) DNA sequencing allele level resolution, HLA Class I (A,B,C) by HLA-Class II (DRB1)HLA-Class II (DQB1)http://www.nybloodcenter.org/HLA-Typing.do?sid0=92&page_id=185

Transplantation Immunology 11

Not all HLA genes are equally importantWhy?

In Kidney -- Little MHC-II expressed 6 HLA antigens examined:

-- HLA-A, HLA-B, and HLA-DR e.g., HLA-A1 & A2, B7 & B8, DR2 & DR3

Liver -- little MHC-I or -II expressed-- usually only ABO matched

What about…Cornea: No matching …Why?

Heart: No matching …Why?

Increased HLA matching yields only minor improvements in

kidney survival