BACKGROUND: A major obstacle to the success of organ transplantation from pigs to humans, necessitated by the shortage of human organs, is robust humoral immune rejection by pig-reactive human antibodies. Mixed xenogeneic hematopoietic chimerism induces xenoreactive B cell tolerance in rodents, but whether mixed pig/human chimerism could induce tolerance of human B cells to pig xenoantigens is unknown. METHODS: We investigated this question using a humanized mouse model in which durable mixed (pig-human) xenogeneic chimerism can be established. RESULTS: Human natural anti-pig cytotoxic antibodies, predominantly IgM, are detectable in non-chimeric humanized mouse serum, and pig-reactive antibodies were reduced in mixed chimeric versus non-chimeric humanized mice. This difference required persistent mixed chimerism and was not due to the adsorption of antibodies on pig cells in vivo. Furthermore, human B cells from spleens of mixed chimeric mice produced lower levels of anti-pig antibodies when stimulated in vitro compared with those from non-chimeric mice. CONCLUSIONS: Our findings demonstrate that mixed chimerism reduces human natural antibodies to pig xenoantigens, providing the first in vivo evidence of human B cell tolerance induction by mixed xenogeneic chimerism and supporting further evaluation of this approach for inducing human B cell tolerance to xenografts.
BACKGROUND: A major obstacle to the success of organ transplantation from pigs to humans, necessitated by the shortage of human organs, is robust humoral immune rejection by pig-reactive human antibodies. Mixed xenogeneic hematopoietic chimerism induces xenoreactive B cell tolerance in rodents, but whether mixed pig/human chimerism could induce tolerance of human B cells to pig xenoantigens is unknown. METHODS: We investigated this question using a humanized mouse model in which durable mixed (pig-human) xenogeneic chimerism can be established. RESULTS: Human natural anti-pig cytotoxic antibodies, predominantly IgM, are detectable in non-chimeric humanized mouse serum, and pig-reactive antibodies were reduced in mixed chimeric versus non-chimeric humanized mice. This difference required persistent mixed chimerism and was not due to the adsorption of antibodies on pig cells in vivo. Furthermore, human B cells from spleens of mixed chimeric mice produced lower levels of anti-pig antibodies when stimulated in vitro compared with those from non-chimeric mice. CONCLUSIONS: Our findings demonstrate that mixed chimerism reduces human natural antibodies to pig xenoantigens, providing the first in vivo evidence of human B cell tolerance induction by mixed xenogeneic chimerism and supporting further evaluation of this approach for inducing human B cell tolerance to xenografts.
Authors: Fan Liang; Isaac Wamala; Joseph Scalea; Aseda Tena; Taylor Cormack; Shannon Pratts; Raimon Duran-Struuck; Nahel Elias; Martin Hertl; Christene A Huang; David H Sachs Journal: Xenotransplantation Date: 2013-10-29 Impact factor: 3.907
Authors: Donna Kolber-Simonds; Liangxue Lai; Steven R Watt; Maria Denaro; Scott Arn; Monica L Augenstein; Jeffery Betthauser; David B Carter; Julia L Greenstein; Yanhong Hao; Gi-Sun Im; Zhonghua Liu; Greg D Mell; Clifton N Murphy; Kwang-Wook Park; August Rieke; David J J Ryan; David H Sachs; Erik J Forsberg; Randall S Prather; Robert J Hawley Journal: Proc Natl Acad Sci U S A Date: 2004-05-03 Impact factor: 11.205
Authors: Julie Lang; Takayuki Ota; Margot Kelly; Pamela Strauch; Brian M Freed; Raul M Torres; David Nemazee; Roberta Pelanda Journal: J Exp Med Date: 2015-12-22 Impact factor: 14.307