B‐Cell Depletion Extends the Survival of GTKO.hCD46Tg Pig Heart Xenografts in Baboons for up to 8 Months

Xenotransplantation of genetically modified pig organs offers great potential to address the shortage of human organs for allotransplantation. Rejection in Gal knockout (GTKO) pigs due to elicited non‐Gal antibody response required further genetic modifications of donor pigs and better control of the B‐cell response to xenoantigens. We report significant prolongation of heterotopic alpha Galactosyl transferase “knock‐out” and human CD46 transgenic (GTKO.hCD46Tg) pig cardiac xenografts survival in specific pathogen free baboons. Peritransplant B‐cell depletion using 4 weekly doses of anti‐CD20 antibody in the context of an established ATG, anti‐CD154 and MMF‐based immunosuppressive regimen prolonged GTKO.hCD46Tg graft survival for up to 236 days (n = 9, median survival 71 days and mean survival 94 days). B‐cell depletion persisted for over 2 months, and elicited anti‐non‐Gal antibody production remained suppressed for the duration of graft follow‐up. This result identifies a critical role for B cells in the mechanisms of elicited anti‐non‐Gal antibody and delayed xenograft rejection. Model‐related morbidity due to variety of causes was seen in these experiments, suggesting that further therapeutic interventions, including candidate genetic modifications of donor pigs, may be necessary to reduce late morbidity in this model to a clinically manageable level.

[1]  A. Kirk,et al.  CD40‐Specific Costimulation Blockade Enhances Neonatal Porcine Islet Survival in Nonhuman Primates , 2011, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[2]  D. Cooper,et al.  Therapeutic issues in the treatment of vascularized xenotransplants using gal-knockout donors in nonhuman primates , 2011, Current opinion in organ transplantation.

[3]  D. Sachs,et al.  Absence of Gal epitope prolongs survival of swine lungs in an ex vivo model of hyperacute rejection , 2011, Xenotransplantation.

[4]  R. F. Hoyt,et al.  Surgical and nonsurgical complications of a pig to baboon heterotopic heart transplantation model. , 2010, Transplantation proceedings.

[5]  E. Cozzi.  On the road to clinical xenotransplantation. , 2009, Transplant immunology.

[6]  Vivek Rao,et al.  Left ventricular device as destination therapy: are we there yet? , 2009, Current opinion in cardiology.

[7]  R. Colvin,et al.  Cardiovascular , Pulmonary and Renal Pathology Thrombotic Microangiopathy Associated with Humoral Rejection of Cardiac Xenografts from 1 , 3-Galactosyltransferase Gene-Knockout Pigs in Baboons , 2010 .

[8]  F. Pagani,et al.  Heart and Lung Transplantation in the United States, 1997–2006 , 2008, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[9]  D. Cooper,et al.  Recent advances in pig-to-human organ and cell transplantation , 2008, Expert opinion on biological therapy.

[10]  M. Mohiuddin.  Clinical Xenotransplantation of Organs: Why Aren't We There Yet? , 2007, PLoS medicine.

[11]  R. Zhong.  Gal Knockout and Beyond , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[12]  D. Sachs,et al.  Elicited Antibodies in Baboons Exposed to Tissues from α1,3-Galactosyltransferase Gene-Knockout Pigs , 2006, Transplantation.

[13]  Keiji Oi,et al.  Cardiac xenotransplantation : Recent preclinical progress with 3-month median survival , 2005 .

[14]  R. Pierson,et al.  Co‐stimulation blockade targeting CD154 and CD28/B7 modulates the induced antibody response after a pig‐to‐baboon cardiac xenograft , 2005, Xenotransplantation.

[15]  B. Loveland,et al.  Characterization of a CD46 transgenic pig and protection of transgenic kidneys against hyperacute rejection in non‐immunosuppressed baboons , 2004, Xenotransplantation.

[16]  D. Adams,et al.  Human membrane cofactor protein (MCP, CD 46) protects transgenic pig hearts from hyperacute rejection in primates , 2001, Xenotransplantation.

[17]  J. Platt.  Genetic engineering for xenotransplantation. , 1999, Transplantation proceedings.

[18]  Platt Jl,et al.  Hyperacute xenograft rejection as an immunologic barrier to xenotransplantation. , 1997 .

[19]  R. Pierson,et al.  Progress towards clinical xenotransplantation. , 2008, Frontiers in bioscience : a journal and virtual library.

[20]  N. Mueller,et al.  Heart transplantation in baboons using α1,3-galactosyltransferase gene-knockout pigs as donors: initial experience , 2005, Nature Medicine.

[21]  E. Ancona,et al.  Xenotransplantation-current status and future perspectives. , 2005, British medical bulletin.

[22]  E. Bloom,et al.  Clinical xenotransplantation. , 2001, JAMA.

[23]  J. Platt,et al.  Hyperacute xenograft rejection as an immunologic barrier to xenotransplantation. , 1997, Kidney international. Supplement.