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PubMed1998

Posttransplant nonfunction of canine islets in PVG rats deficient in complement component C6.

BACKGROUND: Discordant islet xenografts are immediately nonfunctional in nonimmunosuppressed recipients other than the mouse, a process called primary nonfunction. Although at present it is unknown whether complement is involved, complement might participate in the induction of primary nonfunction through a number of mechanisms. We investigated the potential role of the membrane attack complex of complement in primary nonfunction of transplanted xenoislets. METHODS: Canine islets were transplanted into both nonimmunosuppressed and immunosuppressed normocomplementemic and C6-deficient (C6D) PVG rats. Cyclosporine, rapamycin, deoxyspergualin, and mycophenolate mofetil were used for immunosuppression from day -3 to cessation of islet cell function. Serum glucose was measured at 6 hr after transplant and daily thereafter. Xenograft tissue sections were obtained at various times after transplant and stained for inflammatory cells and insulin. RESULTS: Canine islets grafted in nonimmunosuppressed C6D rats and normocomplementemic rats underwent primary nonfunction in all animals. The incidence of primary nonfunction in animals receiving a four-drug immunosuppressive regimen was 33% in the normocomplementemic rats but only 10% in the C6D rats. The mean functional islet survival time was 1.57+/-0.33 days in the normocomplementemic group and 2.70+/-0.67 days in the C6D group (P=0.38). The islet xenografts showed little difference in degree and composition of cell infiltration between normocomplementemic and C6D rats. CONCLUSION: The membrane attack complex does not appear to play a major role in primary nonfunction of canine islet xenografts in nonimmunosuppressed PVG rats. However, there was a lower incidence of primary nonfunction and a longer posttransplant survival time in immunosuppressed C6D rats, suggesting the membrane attack complex may play a minor role in recipients that are heavily immunosuppressed.

Animals↗
PubMed1985

Genetically determined molecular weight differences in murine complement component C6.

Plasma samples from male CBA, BALB/c and DBA/2 mice were subjected to polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. Bands of C6 hemolytic activity in the washed resolving gel were identified by means of an erythrocyte/agarose overlay gel. CBA plasma was found to contain two forms of C6, one with a molecular weight (Mr) of approximately 90 000 (type A) and one with a Mr of 100 000 (type B); CBA mice were thus designated C6: A+B+. BALB/c and DBA/2 plasma on the other hand contained only the low molecular weight type A C6 and were designated C6: A+B-. Flat bed isoelectric focusing followed by functional overlays showed that CBA plasma produced two sets of hemolytic bands (pI 5.25-5.4 and 5.0-5.2) whereas BALB/c and DBA/2 plasma produced only the more cathodal band set. The additional band set in CBA plasma corresponded to the high-Mr type B C6. Results of breeding experiments demonstrated that the possession of the high Mr type B C6 was inherited in the manner of an autosomal phenotypically dominant characteristic.

Animals↗
PubMed1994

Hepatic and extrahepatic biosynthesis of complement factor C6 in the rat.

The relative contributions of liver and bone marrow (BM) constituents to systemic C6 production were compared in a rat model. Liver grafts were transplanted from C6-sufficient PVG (RT1c) rats (PVG (C+)) to profoundly C6-deficient PVG rats (PVG (C-)). C6 levels were restored to 32% within 24 h and reached more than 80% of that of the PVG (C+) donor within 7 days post-grafting, which indicates that the liver is a primary source of systemic C6 production. When livers were transplanted from PVG (C-) to PVG (C+) rats (n = 3), levels of C6 dropped to 42% of pretransplant levels within 24 h and remained between 30 and 40% for more than 100 days after grafting. To determine the source of extrahepatic C6 production, BM was transplanted from PVG (C+) to PVG (C-) rats after total body irradiation. Levels of C6 increased from undetectable levels to 5% of C6 levels of the donor PVG (C+) rat within 60 days. Replenishing PVG (C-) recipients with BM after treatment of recipients with busulfan, which preferentially allows reconstitution with donor myelomonocyte stem cells, resulted in restoration of C activity. Treatment with cyclophosphamide before BM transplantation, which preferentially allows reconstitution of lymphoid stem cells, did not restore hemolytic C activity in PVG (C-) rats. These results were confirmed directly by the successful restoration of C activity with BM depleted of lymphocytes by counterflow centrifugal elutriation from PVG (C+) rats. These in vivo experiments demonstrate that the liver is a primary, but not the sole, source of C6 in the rat and that extrahepatic sources, such as myelomonocytes, and not lymphoid cells in the BM produce a significant amount of systemic C6 in the rat.

Animals↗
PubMed2000

Complement component C6 polymorphism: novel protein-typing technique and distribution of allotypes in Germany.

The genetic polymorphism of human C6 was investigated in Germany using an improved technique: polyacrylamide gel isoelectric focusing and subsequent direct immunofixation with monospecific C6 antisera. Typing of C6 was performed on native serum samples from 1,775 unrelated persons. The gene frequencies in the population study were as follows: C6*A 0.6313, C6*B 0.3566 and the rare alleles C6*R 0. 0121. In total, 8 rare allotypes were analysed. The gene frequencies obtained are in good agreement with those previously published.

Alleles↗
PubMed1985

Assignment of the gene locus for the sixth component (C6) of complement in mice to chromosome 15.

A structural locus (C-6) for the sixth component of complement in mice is assigned to chromosome 15. Three-point linkage analysis indicated that the order of loci is C-6, Gpt-1, Gdc-1, and that the map distances are 25.9 +/- 4.9 between C-6 and Gpt-1, and 36.4 +/- 5.5 between C-6 and Gdc-1. Since Gdc-1 is more distal than Gpt-1, and C-6 is 26 cM away from Gpt-1, it is estimated that the C-6 is proximal to the centromere. In addition, a new C6 form found in AKR mice is described. We propose the designation C6B for it and C-6b for the allele encoding C6B.

Alanine Transaminase↗
PubMed1983

Polymorphism of the complement component C6 in Japanese.

Genetic polymorphism of human C6 was investigated in Japanese using isoelectric focusing and a specific haemolytic overlay method. Three common and six rare allotypes were identified. Five of these nine allotypes were reference-typed by the International Reference Laboratory. Five of the six rare allotypes were considered to be new. The allele frequencies were estimated in the population study as follows: C6 A 0.427, C6 B 0.483, C6 B2 0.076, and the rare alleles (A3, A21, M1, M2, B3, and B4) 0.014. Inheritance of the three common and the two rare (A3 and M1) allotypes was demonstrated in the family study. The patterns obtained by the pretreatment with neuraminidase are presented.

Alleles↗
PubMed1983

Immunological detection of the sixth complement component (C6) following flat bed polyacrylamide gel isoelectric focusing and electrophoretic transfer to nitrocellulose filters.

A method for the electrophoretic transfer of C6 molecules to a nitrocellulose filter is described. The protein is detected by the use of anti-C6 antibodies and a peroxidase conjugated antibody. Using this method typical isoelectric patterns of C6 variant phenotypes are found. Inheritance and population data are presented. Three rare structural variants, one of which appears to be previously unreported, were discovered among a sample of 202 individuals. The method is discussed from the viewpoint of its flexibility and its value as an additional tool for revealing inherited variations in structural gene products.

Antibodies↗
PubMed1987

Human alveolar macrophages synthesize active complement components C6, C7, and C8 in vitro.

We investigated whether serum-free human alveolar macrophage cultures synthesize active C6, C7, and C8. There was a significant binding of polyclonal anti-human C6 antibodies to agarose beads incubated with unstimulated macrophages for 24 or 48 h. Endotoxin stimulation of the macrophages was necessary for significant binding of polyclonal anti-C7 and anti-C8 antibodies to agarose beads co-cultured for 48 or 96 h. Two monoclonal antibodies (poly C9-MA and MCaE11) specific for a neoantigen of polymerized C9 in the terminal complement complex (TCC), bound to beads mainly incubated with endotoxin stimulated macrophages. The MCaE11 was more sensitive than the poly C9-MA in detecting the C9 neoantigen on beads incubated with the macrophages or human serum diluted 1:16. We thus conclude that human alveolar macrophages synthesize active C6, C7, and C9 that together with C5 and C9, assemble as the TCC on co-cultured agarose beads. Activation of the alternative pathway on the agarose with generation of fixed C3 and C5 convertases is a prerequisite for the subsequent generation of the TCC.

Adult↗
PubMed1994

C6 haplotypes: associations of a Dde I site polymorphism to complement deficiency genes and the Msp I restriction fragment length polymorphism (RFLP)

Complement C6 has a common charge polymorphism designated A and B with gene frequencies of 0.65 and 0.35. The probable molecular basis for this is a Glu (C6A) for Ala (C6B) substitution at amino acid position 98, and is detected by digestion with the restriction enzyme Dde I of a polymerase chain reaction (PCR)-amplified fragment of genomic DNA. C6A was found to be Dde I-positive and C6B corresponds to Dde I-negative. We have applied our Dde I A/B polymorphism genotyping method to the investigation of C6-deficient individuals with complete (C6Q0) and sub-total deficiency (C6SD) protein phenotypes, including members of four families. We have also investigated the RFLP detected by digestion of genomic DNA with the enzyme Msp I, which is due to a polymorphic site located in the 5' section of the gene, the variable sequence of which has yet to be determined. Sixteen out of seventeen unrelated C6Q0 subjects were found to be genotypically Dde I B/Msp I-negative; the remaining subject was heterozygous at both the loci under investigation. The C6SD phenotype was found to be associated with the Dde I A/Msp I-positive genotype in two families with combined C6/C7 subtotal deficiency and two with C6SD. It can be concluded that the two forms of C6 deficiency, C6Q0 and C6SD, arose independently on two different C6 allelic backgrounds. These associations have allowed the genotyping of the rare families that contain both types of deficiency. We have also defined a number of normal C6 Dde I/Msp I haplotypes in Caucasians and Cape Coloured populations.

Adult↗
PubMed1999

Hyperacute rejection in the guinea pig-to-rat model without formation of the membrane attack complex.

The guinea pig (GP)-to-rat transplantation model has been widely used to study hyperacute rejection (HAR) of xenografts. In this model heart graft survival beyond 8 days has never been reported. In contrast, survival times of kidney and heart grafts up to 62 days have been reported in the discordant pig-to-primate model. It is not clear why it is so much more difficult to obtain long-term graft survival in the GP-to-rat model as compared to the pig-to-primate model. We hypothesized that mechanisms other than activation of complement may be involved in the rejection of guinea pig grafts by rat recipients. Therefore, we have studied in detail the rejection of GP aortic grafts by rat recipients, either PVG/c+ (complement competent, group 1), or PVG/c- (complement C6 deficient, group 2). PVG/c- rats are not able to form the membrane attack complex (MAC) of complement. Forty-four GP-to-rat aortic transplantations were performed successfully. Recipient rats were sacrificed at various intervals after transplantation (4, 24 and 48 h, and 7 and 28 days, three to six animals per time point per group). Twenty-four hours after transplantation the number of cells in the media was significantly decreased from 11.1 +/- 0.9 cells/mm2 to 3.1 +/- 2.8 cells/mm2 in group 1, whereas the number of medial cells in group 2 remained the same. The number of medial cells was significantly decreased in both groups at 48 h post-transplantation (group 1: 1.8 +/- 2.2 cells/mm2; group 2: 5.5 +/- 3.0 cells/mm2). At that time no infiltrating cells were apparent in the grafts of either two groups. Seven days after transplantation, the number of medial cells remained low in group 1 (1.8 +/- 2.9 cells/mm2) but was increased in group 2 (10.7 +/- 2.6 cells/mm2) as a consequence of infiltrating immune cells. These infiltrating cells consisted mainly of macrophages, but also T cells and NK cells. At 28 days after transplantation the grafts in both groups were completely reorganized and no distinction could be made between media and adventitia. These results show that rejection of GP grafts by rat recipients can occur in the absence of both MAC of complement and immune competent cells. This MAC and immune cells independent type of rejection has not been described before and may explain the difficulty in obtaining long-term graft survival in the GP-to-rat xenotransplantation model.

Acute Disease↗
PubMed1982

Combined hereditary deficiency of the sixth component of complement and factor VIII coagulant activity in a Dutch family.

Prompted by previous observations of defective blood clotting in rabbits deficient in the sixth component of complement (C6), and the discovery of a patient with both C6 and factor VIII deficiency, an evaluation was made of the haemostatic functions in this individual and his family members. The family contained three members homozygous for C6 deficiency (C6D); two of them were deficient also in factor VIII. In addition, one other member of the family was only deficient in factor VIII. The only C6D member without haemophilia A had a normal recalcification time without clinical symptoms of a bleeding disorder. Reconstitution of factor VIII and C6 deficient plasma from the various members of the family in this study with purified human C6 did not result in a change in the recalcification time. The results obtained from this study also indicate that there is no linkage between the inheritance of C6 and factor VIII.

Adult↗
PubMed2004

Molecular basis for complement component 6 (C6) deficiency in rats and mice.

Complement component C6 is a part of the lytic membrane attack complex formed during complement activation. Animal modeling to define the role of C5a vs. C5b-9 in human disease has used rodents deficient in C6, yet the molecular basis for the deficiencies has not been ascertained. Oligonucleotides derived from a 493 bp EST sequence of the rat C6 gene were used to isolate full-length transcripts of rat C6 mRNA. Sequence analysis confirmed that the derived amino acid sequence for rat C6 is highly homologous to human and mouse. We identified a 31 bp deletion in exon 10 of the C6 gene that leads to C6 deficiency in a strain of PVG rats (PVG/c-) and developed a PCR-based genotyping test. In addition, we identified four point mutations in the mouse C6 gene that may result in C6 deficiency observed in the Peru-Coppock mouse strain. A serendipitous finding from this study was a coagulation defect in the C6 deficient mice and rats. C6 deficient mice or rats demonstrated prolonged tail bleeding times that was reversed by treatment with purified rat C6 protein. Further, adenosine diphosphate induced platelet aggregation were markedly reduced in C6 deficient rats. The molecular basis for these coagulations defects is unknown at present.

Amino Acid Sequence↗
PubMed1982

Genetic control of C6 polymorphism and C6 deficiency in rabbits.

The genetic control of the sixth component of complement (C6) in rabbits has been studied by quantitation of C6 functional and antigenic levels and identification of polymorphism by isoelectric focusing (IEF) in gels. Patterns of inheritance of C6 variants in families carrying a silent gene for C6 were examined, and it was found that 3 common plasma phenotypic variants, C6 A, C6 B, and C6 QO were under the genetic control of allelic genes, C6*A, C6*B, and C6*QO. In IEF patterns, C6 A could be identified by its isoelectric point that was slightly more acidic than that of C6 B. C6 QO was undetectable because it lacked functional and antigenic activity. The C6*A/C6*B genotype displayed a mixed IEF pattern with bands characteristic of both C6 A and C6 B. Functional and antigenic levels of C6 that were found in heterozygous C6*A/C6*QO and C6*B/C6*QO rabbits were approximately one-half of the C6 levels found in the corresponding homozygous animals. The phenotypic variation closely resembles that previously observed in humans and rhesus monkeys, as well as preliminary data in rabbits. The patterns of inheritance indicated that the two common C6 structural genes and the deficiency gene were allelic variants at the same genetic locus.

Animals↗
PubMed1998

The molecular basis of C6 deficiency in the western Cape, South Africa.

Deficiency of the sixth component of human complement (C6) has been reported in a number of families from the western Cape, South Africa. Meningococcal disease is endemic in the Cape and almost all pedigrees of total C6 deficiency (C6Q0) have been ascertained because of recurrent disease. We have sequenced the expressed exons of the C6 gene from selected cases and have found three molecular defects leading to total deficiency: 879delG, which is the common defect in the Cape and hitherto unreported, and 1195delC and 1936delG, which have been previously reported in African-Americans. We also show that the 879delG and 1195delC defects are associated with characteristic C6/C7 region DNA marker haplotypes, although small variations were observed. The 1936delG defect was observed only once in the Cape, but its associated haplotype could be deduced. The data from the haplotypes indicate that these three molecular defects account for the defects in all the 38 unrelated C6Q0 individuals we have studied from the Cape. We have also observed the 879delG defect in two Dutch C6-deficient kindreds, but the 879delG defect in the Cape probably did not come from The Netherlands.

Base Sequence↗