Cardiac xenotransplantation: recent preclinical progress with 3-month median survival.
OBJECTIVE
Transplantation is limited by a lack of human organ donors. Organs derived from animals, most likely the pig, represent a potential solution to this problem. For the heart, 90-day median graft survival of life-supporting pig hearts transplanted to nonhuman primates has been considered a reasonable standard for entry into the clinical arena. Overcoming the immune barrier to successful cardiac xenotransplantation is most appropriately first explored with the non-life-supporting heterotopic model.


METHODS
We performed a series of 7 heterotopic heart transplantations from CD46 transgenic pigs to baboons using a combination of therapeutic agents largely targeted at controlling the synthesis of anti-pig antibodies. Rituximab (anti-CD20) and Thymoglobulin (rabbit antithymocyte globulin [ATG]; SangStat Medical Corp, Fremont, Calif) were used as induction therapy. Baseline immunosuppression consisted of splenectomy, tacrolimus, sirolimus, steroids, and TPC (an anti-Gal antibody therapeutic). Rejection events were not treated.


RESULTS
By using Kaplan-Meier analysis, median graft survival was 96 days (range, 15-137 days; 95% confidence interval, 38-99 days). Only 2 grafts were lost as a result of rejection, as defined by cessation of graft palpation. There was no evidence of a consumptive coagulopathy, infectious complications were treatable, and no posttransplantation lymphoproliferative disorders occurred. No cellular infiltration was observed.


CONCLUSIONS
This study reports the longest median survival to date (96 days) of pig hearts transplanted heterotopically into baboons. Duplication of these results in the orthotopic life-supporting position could bring cardiac xenotransplantation to the threshold of clinical application.
McGregor
Christopher G A
CG
Division of Cardiovascular Surgery, Department of Surgery, Mayo Clinic, Rochester, Minn 55905, USA. mcgregor.christopher@mayo.edu
Davies
William R
WR
Oi
Keiji
K
Teotia
Sumeet S
SS
Schirmer
Johannes M
JM
Risdahl
Jack M
JM
Tazelaar
Henry D
HD
Kremers
Walter K
WK
Walker
Randall C
RC
Byrne
Guerard W
GW
Logan
John S
JS
D000818:Animals; D030801:Animals, Genetically Modified; D000906:Antibodies / Q000627:therapeutic use; D015703:Antigens, CD / Q000235:genetics; D004187:Disaccharides / Q000276:immunology; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival; D016027:Heart Transplantation / Q000401:mortality / Q000473:pathology; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000235:genetics; D009200:Myocardial Contraction; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D010215:Papio; D015996:Survival Rate; D013552:Swine / Q000235:genetics; D014183:Transplantation, Heterologous / Q000401:mortality / Q000473:pathology; D016042:Transplantation, Heterotopic
D000906:Antibodies; D015703:Antigens, CD; D004187:Disaccharides; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; C055075:galactosyl-(1-3)galactose