Cytoplasmic inheritance of transplantation antigens in animals produced by nuclear transfer.
BACKGROUND
Nuclear transfer has been used as a means of selectively modifying the mammalian genome. One possible consequence of this technology is that the oocytes used in nuclear transfer may provide additional antigens by cytoplasmic inheritance of maternally derived, mitochondrial DNA (mtDNA). These studies examine the potential consequences of such inheritance in a large animal transplantation model.


METHODS
Renal transplants were performed between major histocompatibility complex (MHC)-identical animals differing only in the source of their maternally derived cytoplasmic DNA, using a protocol, which uniformly leads to tolerance within standard MHC-inbred lines. In an attempt to correlate transplant results with a putative marker for disparities in cytoplasmically inherited minor histocompatibility antigens, we examined one hypervariable region of mtDNA, designated hypervariable region 1 (HV1).


RESULTS
The mtDNA sequence of the HV1 region was found to be invariant among MGH miniature swine of different haplotypes, despite 25 years of selective breeding of the sublines of this colony. In contrast, swine derived by nuclear transfer into outbred oocytes differed in the HV1 region sequence from each other and from MGH swine. Renal transplants from standard, inbred MGH swine to their MHC-identical knockout counterparts derived from outbred oocytes were rejected within 2 weeks, whereas transplants in the reverse direction were accepted for over 30 days.


CONCLUSIONS
The HV1 sequence of mtDNA may serve as a marker for the level of diversity of mtDNA. These transplant data are consistent with the existence of mtDNA-encoded mitochondrial minor antigens with a level of diversity that can influence the outcome of renal transplantation.
Hanekamp
John S
JS
Transplantation Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. John.hanekamp@tbrc.mgh.harvard.edu
Okumi
Masayoshi
M
Tena
Aseda
A
Arn
Scott
S
Yamada
Kazuhiko
K
Sachs
David H
DH
D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D016572:Cyclosporine / Q000494:pharmacology; D004272:DNA, Mitochondrial; D005111:Extrachromosomal Inheritance; D005260:Female; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics; D055786:Gene Knockout Techniques; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology; D006085:Graft Survival / Q000235:genetics* / Q000276:immunology; D006239:Haplotypes; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D000949:Histocompatibility Antigens Class II; D006720:Homozygote; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016030:Kidney Transplantation; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000276:immunology; D008969:Molecular Sequence Data; D053652:Nuclear Transfer Techniques; D010375:Pedigree; D013552:Swine; D013556:Swine, Miniature / Q000235:genetics; D013997:Time Factors; D023001:Transplantation Tolerance / Q000235:genetics; D014184:Transplantation, Homologous
D004272:DNA, Mitochondrial; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D024101:Mitochondrial Proteins; C438668:swine leukocyte antigen; D016572:Cyclosporine; D005700:Galactosyltransferases; C530267:alpha-1,3-galactosyltransferase 1, porcine