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The anti-non-gal xenoantibody response to xenoantigens on gal knockout pig cells is encoded by a restricted number of germline progenitors.

ABSTRACT: Antibodies directed at non-gal xenoantigens are responsible for acute humoral xenograft rejection when gal knockout (GalTKO) pig organs are transplanted into nonhuman primates. We generated IgM and IgG gene libraries using peripheral blood lymphocytes of rhesus monkeys initiating active xenoantibody responses after immunization with GalTKO pig endothelial cells and used these libraries to identify IgV(H) genes that encode antibody responses to non-gal pig xenoantigens. Immunoglobulin genes derived from the IGHV3-21 germline progenitor encode xenoantibodies directed at non-gal xenoantigens. Transduction of GalTKO cells with lentiviral vectors expressing the porcine alpha1,3 galactosyltransferase gene responsible for gal carbohydrate expression results in a higher level of binding of 'anti-non-gal' xenoantibodies to transduced GalTKO cells expressing the gal carbohydrate, suggesting that anti-non-gal xenoantibodies cross react with carbohydrate xenoantigens. The galactosyltransferase two gene encoding isoglobotriaosylceramide synthase (iGb3 synthase) is not expressed in GalTKO pig cells. Our results demonstrate that anti-non-gal xenoantibodies in primates are encoded by IgV(H) genes that are restricted to IGHV3-21 and bind to an epitope that is structurally related to but distinct from the Gal carbohydrate.

SUBMITTER: Kiernan K

PROVIDER: S-EPMC3462011 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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The anti-non-gal xenoantibody response to xenoantigens on gal knockout pig cells is encoded by a restricted number of germline progenitors.

Kiernan K K Harnden I I Gunthart M M Gregory C C Meisner J J Kearns-Jonker M M

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20080728 9

Antibodies directed at non-gal xenoantigens are responsible for acute humoral xenograft rejection when gal knockout (GalTKO) pig organs are transplanted into nonhuman primates. We generated IgM and IgG gene libraries using peripheral blood lymphocytes of rhesus monkeys initiating active xenoantibody responses after immunization with GalTKO pig endothelial cells and used these libraries to identify IgV(H) genes that encode antibody responses to non-gal pig xenoantigens. Immunoglobulin genes deriv ...[more]

PMID: 18671678

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Project description:The natural anti-Gal antibody is one of the multiple natural anti-carbohydrate antibodies produced in humans against a wide range of carbohydrate antigens on GI bacteria. The antibody is unique to humans, apes, and Old World monkeys, and it binds specifically to a mammalian carbohydrate antigen called the ?-gal epitope that is synthesized in nonprimate mammals, lemurs (prosimians) and New World monkeys by the glycosylation enzyme ?1,3GT. The ?1,3GT gene (GGTA1) appeared in mammals >100 million years ago, prior to the split between marsupial and placental mammals. This gene has been conserved in its active form, in all mammals, except for Old World monkeys, apes, and humans. Inactivation of the ?1,3GT gene in ancestral Old World primates occurred 20–30 million years ago and could have been associated with epidemics of enveloped viruses in the Eurasia-Africa continent. It is suggested that prior to such epidemics, few ancestral Old World primates acquired deletion point mutations that inactivated the ?1,3GT gene and eliminated ?-gal epitopes. This resulted in loss of immune tolerance to the ?-gal epitope and thus, in production of the anti-Gal antibody against antigens on bacteria colonizing the GI tract. This accidental inactivation of the ?1,3GT gene in very small populations is analogous to the highly rare blood type “Bombay” individuals who do not synthesize blood group H (O antigen) because of inactivation of the ?1,2-fucosyltransferase gene. The loss of immune tolerance to blood group H antigen has resulted in production of natural anti-blood group H antibodies in the blood group Bombay individuals. It is suggested that anti-Gal protected against infections by enveloped viruses presenting ?-gal epitopes, which were lethal to the parental primate populations that conserved active ?1,3GT and thus, synthesized ?-gal epitopes. Alternative causes for the elimination of Old World primates synthesizing ?-gal epitopes could be bacteria or protozoa parasites presenting ?-gal or ?-gal-like epitopes, and bacterial toxins, or detrimental viruses that used ?-gal epitopes in these primates as “docking receptors.” Ultimately, any of these proposed selective processes could result in extinction of Old World primates synthesizing ?-gal epitopes on their cells. These ancestral primates were replaced by offspring populations lacking ?-gal epitopes and producing the anti-Gal antibody, which continues to be produced by Old World monkeys, apes, and humans. New World monkeys and lemurs were protected from pathogens of the Old World by oceanic barriers, thus they continue to synthesize ?-gal epitopes and lack the ability to produce the anti-Gal antibody. This scenario of few individuals in a large population having a mutation(s) that inactivates a glycosyltransferase gene thus, resulting in production of evolutionary advantageous natural antibodies against the eliminated carbohydrate antigen, may reflect one of the mechanisms inducing changes in the carbohydrate profile of various mammalian populations.

Project description:The ?-Gal epitope (Gal?1,3Gal?1,4GlcNAc?R) is ubiquitously presented in non-primate mammals, marsupials and New World Monkeys, but it is absent in humans, apes and Old World monkeys. However, the anti-Gal antibody (~1% of immunoglobulins) is naturally generated in human, and is found as the immunoglobulin G (IgG), IgM and IgA isotypes. Owing to the specific binding of the anti?Gal antibody with the ??Gal epitope, humans have a distinct anti???gal reactivity, which is responsible for hyperacute rejection of organs transplanted from ??gal donors. In addition, the ?1,3 galactosyltransferases (?1,3GT) can catalyze the synthesis of the ??Gal epitope. Therefore, the ?1,3GT gene, which encodes the ?1,3GT, is developed profoundly. The distributions of the ??Gal epitope and anti?Gal antibody, and the activation of ?1,3GT, reveal that the enzyme of ?1,3GT in ancestral primates is ineffective. Comparison of the nucleotide sequence of the human ?1,3?GT pseudogene to the corresponding different species sequence, and according to the evolutionary tree of different species, the results of evolutionary inactivation of the ?1,3GT gene in ancestral primates attribute to the mutations under a stronger selective pressure. However, on the basis of the structure, the mechanism and the specificity of the ??Gal epitope and anti?Gal antibody, they can be applied to clinical exploitation. Knocking out the ?1,3GT gene will eliminate the xenoantigen, Gal(?1,3)Gal, so that the transplantation of ?1,3GT gene knockout pig organ into human becomes a potential clinically acceptable treatment for solving the problem of organ shortage. By contrast, the ??Gal epitope expressed through the application of chemical, biochemical and genetic engineering can be exploited for the clinical use. Targeting anti?Gal?mediated autologous tumor vaccines, which express ??Gal epitope to antigen?presenting cells, would increase their immunogenicity and elicit an immune response, which will be potent enough to eradicate the residual tumor cells. For tumor vaccines, the way of increasing immunogenicity of certain viral vaccines, including flu vaccines and human immunodeficiency virus vaccines, can also be used in the elderly. Recently, ??Gal epitope nanoparticles have been applied to accelerate wound healing and further directions on regeneration of internally injured tissues.

Dataset Information

The anti-non-gal xenoantibody response to xenoantigens on gal knockout pig cells is encoded by a restricted number of germline progenitors.

Publications

The anti-non-gal xenoantibody response to xenoantigens on gal knockout pig cells is encoded by a restricted number of germline progenitors.

Similar Datasets

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