The use of pig heart xenografts in humans may solve in the future the problem of paucity of heart allografts. Currently, binding of the human natural anti-Gal antibody to alpha-gal epitopes (Gal al-3Gal p14GlcNAc-R) on pig cells results in the immune rejection of xenografts. This obstacle can not be overcome by removal of anti-Gal by affinity columns, because this antibody returns to its normal level within few days. Furthermore, the xenograft recipient produces large amounts of high affinity anti-Gal IgG in response to alpha-gal epitopes on the xenograft. This elicited anti-Gal effectively mediates delayed and chronic rejection of xenografts. We propose to prevent anti-Gal production in xenograft recipients by specific elimination of B cells producing this antibody (designated anti-Gal B cells). This may be achieved by in vivo targeting of an alpha-gal coupled toxin, ricin A, (a-gal-ricin) to B cell receptors (BCR) on anti-Gal B cells, subsequent endocytosis of the toxin and death of these cells. Furthermore, the elimination of mature anti-Gal B cel}s may create a window of opportunity for long term prevention of maturation of these cells. Circulating glycoproteins expressing alpha-gal epitopes, continuously released from the xenograft, may bind to BCR on immature anti-Gal B cells and induce specific apoptosis of these B cells. We will test this hypothesis in alpha-l,3-galactosyltransferase knock-out (KO) mice .
Our aims are 1) to define the optimal a-gal-ricin treatment protocol for elimination of mature anti-Gal B cells and plasma cells, 2) to determine whether infused alpha-gal glycoproteins, or such glycoproteins released from wild type mouse heart allografts, can induce long term elimination of immature anti-Gal B cells, and 3) to determine whether a-gal-ricin treatment can affect survival of pig single cell xenografts in KO mice. Success in these studies will help in planning effective treatments for preventing anti-Gal response in primate xenografts recipients. |

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045849-02
Application #
6475537
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Koh, Crystal Y
Project Start
2000-12-15
Project End
2003-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
2
Fiscal Year
2002
Total Cost
$253,750
Indirect Cost
Name
Rush University Medical Center
Department
Type
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
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