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PubMed1997

Contribution of activated macrophages to the process of delayed xenograft rejection.

BACKGROUND: When hyperacute rejection, involving natural xenoreactive antibodies (XAb) and/or complement (C), can be prevented, xenografts (Xgs) undergo delayed xenograft rejection associated with a progressive mononuclear cell infiltration. We have previously shown that XAb formation can be totally suppressed in leflunomide (LF)-treated, T-deficient nude rats receiving hamster hearts. Hence, this model was well-suited to study a role played by other factors, e.g., natural killer (NK) cells and macrophages (Mphi). The relative contribution of Mphi to delayed xenograft rejection was investigated. METHODS: In addition to LF (20 mg/kg/24 hr p.o.), anti-asialoGM-1 serum (1 mg/48 hr i.v.) and N omega-nitro-L-arginine methyl ester (L-NAME; 100 mg/kg/24 hr i.v.) were given. Graft-infiltrating cells, deposition of cytokines (interferon-gamma [IFN-gamma] and tumor necrosis factor-alpha [TNF-alpha]), IgM and C, and expression of endothelial cell (EC) P- and E-selectins were investigated by immunohistochemistry. In some cases, rat rTNF-alpha or anti-TNF-alpha antibodies were injected intravenously. RESULTS: Xgs rejected after 3 days by LF-treated rats showed an absence of IgM, C, and T cells, but the infiltration of NK cells and Mphi, together with the presence of IFN-gamma and TNF-alpha. Addition of NK cell depletion resulted in a significantly prolonged survival of Xgs (6 days; P<0.001) in which NK cells and IFN-gamma had disappeared, but Mphi were still prominent. Additional blockade of Mphi nitric oxide (NO) with L-NAME further prolonged Xg survival (11 days; P<0.001). In these rejected Xgs, Mphi, TNF-alpha, and EC expression of P- and E-selectins was still found, together with platelet thrombi, neutrophil-EC adhesion, and vessel intima lesions. The role of TNF-alpha in initiating this Xg rejection was further demonstrated by the acceleration of Xg rejection after injection of rTNF-alpha and by a synergism between L-NAME and anti-TNF-alpha antibodies in hampering the acceleration of Xg rejection seen after transfer of sensitized Mphi. CONCLUSION: In the absence of XAb, T cells, and NK cells, Mphi can still reject Xgs. Both NO-dependent and NO-independent mechanisms are involved. In the latter case, Mphi-derived, TNF-alpha-associated EC activation may play a role.

Animals↗
PubMed1993

Chronic meningococcemia in a child with a deficiency of the sixth component of complement.

Chronic meningococcemia represents an uncommon manifestation of meningococcal disease. Microbial and host factors which may predispose to this form of meningococcal disease are not understood. Although acute meningococcal disease is frequently found in patients with terminal complement deficiencies, the relationship of chronic meningococcemia to complement deficiencies is unclear. We present a case report and a review of the literature describing chronic meningococcemia in association with deficiencies of the complement system. A total of eight cases were identified, all of whom were male. Six of the eight patients were children and two of the eight had a previous history of meningococcal disease. This case report, in conjunction with the previously reported cases, suggests an association between complement deficiencies and chronic meningococcemia.

Bacteremia↗
PubMed1992

Antibodies to meningococcal class 1 outer membrane proteins in South African complement-deficient and complement-sufficient subjects.

Inhibition assays were used to investigate human serum antibodies to the meningococcal class 1 outer membrane proteins. We adapted the whole-cell enzyme-linked immunosorbent assay technique to determine the ability of sera to inhibit the binding of murine subtyping monoclonal antibodies. Serum samples from 33 South African subjects with a deficiency in the sixth component of complement as well as serum samples from various groups of complement-sufficient subjects were investigated. Subjects were subdivided according to whether they were (i) convalescent from Neisseria meningitidis infections, (ii) nonconvalescent, or (iii) controls. Preliminary subtyping investigations had shown that P1.2 was present on 36% of meningococcal clinical isolates from Cape Province, South Africa. Assays with the anti-P1.2 antibodies showed the presence of high antibody levels in many deficient sera and moderately elevated levels in some sera from the complement-sufficient convalescent patients. P1.2, P1.4, P1.15, and P1.16 are epitopes situated on loop 4 of the class 1 outer membrane proteins, whereas P1.7 is on loop 1. Inhibition assays showed that human sera that inhibited binding by P1.2 monoclonal antibodies tended to inhibit the other monoclonal antibodies directed to loop 4 epitopes. This suggests that the epitopes recognized by the human antibodies are not exactly the same as the epitopes recognized by the murine monoclonal antibodies and raises the possibility of the importance of other epitopes.

Antibodies, Bacterial↗
PubMed1999

Analysis of fast synaptic pathways in myenteric plexus of guinea pig ileum.

Most fast excitatory postsynaptic potentials (fEPSPs) recorded from guinea pig ileum myenteric plexus are mediated by acetylcholine acting at nicotinic receptors and ATP acting at P2X receptors. These studies examine length and polarity of projection of neurons releasing mediators of fEPSPs. Under ketamine-xylazine anesthesia, animals were sham treated or myenteric pathways were interrupted. After severed axons degenerated, fEPSPs were recorded at the operated site using conventional, intracellular electrophysiological methods and were classified as nicotinic or mixed on the basis of sensitivity to hexamethonium. Cholinergic and noncholinergic fEPSPs were recorded from small, operated segments, suggesting that some neurons have projections between adjacent ganglia. The mean amplitudes of nicotinic and mixed fEPSPs were reduced after circumferential and descending pathways degenerated. The proportion of nicotinic vs. mixed fEPSPs recorded from tissues lacking descending projections was greater than that recorded from sham-treated tissues, suggesting that fibers releasing noncholinergic mediators project aborally. Descending projections communicate with neurons in ganglia at least three rows aboral to their origin. The data suggest that fast noncholinergic neurotransmission could contribute to hexamethonium-resistant descending inhibition during the peristaltic reflex.

Animals↗
PubMed1988

Studies on the formation of a unique cellular intermediate (EAC14256) from EAC142 and C56.

The binding reaction of C56 to EAC142 was studied. The following was observed: (1) C56 can bind to EAC142, without participation of C3 or C7, to form EAC14256; (2) the efficiency of EAC14256 formation from EAC142 and C56 depends highly on the ionic strength of the buffer; (3) EAC14256, generated from EAC142 and C56, decays spontaneously by elution of C56 into the medium and thus the reaction between C56 and EAC142 is reversible; (4) the receptor on EAC142 for C56 is C2 or C42 on the cell surface, and (5) the binding of C56 to C2 or C42 on cells is independent of the usual (C3-dependent) complement cascade activation. These observations, together with the results of our previous report, indicate that the binding of C56, generated from the activation of C5 by C42 (without C3), to EAC142 may be the initial step of membrane attack complex formation in C3-independent immune hemolysis.

Antibodies↗
PubMed1980

Distribution of complement C'2 and C'6 types in Australian cases of diabetes mellitus.

A series of patients with juvenile onset diabetes (IDDM) and mature onset diabetes (NIDDM) have been typed for genetic variants of two sets of complement factors. For the HLA-linked C'2 system, there was found a significant increase of the C'2 2-1 type in IDDM compared with NIDDM patients or healthy controls. No such increase in any phenotype was observed for the non-HLA-linked C'6 system. These observations emphasize again the genetic distinction between IDDM and NIDDM, and the role of chromosome 6 in controlling susceptibility to the insulin-dependent form of the disease.

Alleles↗
PubMed1977

Characterization of human adenoid cells using surface and functional markers for lymphocyte subpopulations.

Adenoid lymphocytes from children undergoing adenoidectomy were compared with blood cells from the same children using techniques for identifying T cells and B cells. A high proportion of adenoid lymphocytes were immunoglobulin positive cells. Of these only a minor fraction carried receptors for the Fc part of IgG. Adenoid B lymphocytes respond poorly if at all to polyclonal B-cell activators, such as LPS or PPD, which show a different reactivity compared to human splenic cells. The response to anti B2-microglobulin was also different; blood cells responded better than adenoid cells. Thus distinct subpopulations of B lymphocytes reside in different lymphoid organs. The adenoid lymphocyte reactivity might reflect their function in the defence mechanism against infections.

Adenoids↗
PubMed1980

Role of C3 in the regulation of a splenic PFC response in rabbits.

The effects of in vivo C3 depletion on the immune response were examined in rabbits by assaying for splenic PFC after immunizing normal or cobra venom factor-treated animals with aggregated human gamma-globulin. The response to this T-dependent antigen has previously been shown to be regulated such that several cycles of PFC appear following a single intravenous injection of antigen. C3 depletion had no effect on the first peak of PFC (appearing 5 days after injection), but resulted in depression of the second peak of PFC (day 13). In rabbits depleted of C3, antigen localization in splenic germinal centers was markedly decreased. Delaying C3 depletion until after antigen localization had occurred resulted in no depression of the second peak of PFC. These results suggest that one mechanism by which C3 affects immune responses in vivo is via its role in influencing the persistence of antigen. In the absence of C3, no significant localization of antigen occurs, resulting in interference with the cyclical production of antibody.

Animals↗
PubMed1980

Mechanism of lethal effect of human serum upon Leishmania donovani.

In order to gain greater understanding of potential host defense mechanisms against Leishmania donovani, we examined the effect of nonimmune, human serum upon promastigotes and amastigotes. Fresh sera were found to be lethal for promastigotes, but had no detectable effect on amastigotes. Serum exposed promastigotes became immotile, did not take up neutral red dye, appeared to be disrupted, and failed to recover after further incubation in fresh media. Heat labile components were required for promastigote killing since heat-inactivated serum (56 degrees C, 30 min) agglutinated but did not kill them. Sera that lacked either the 5th or 6th complement (C) component had no effect when used alone, but when used together, were lethal, indicating that activation of the membrane attack complex (C5b-C9) ws necessary for the lethal effect. The mode of C activation was determined by using serum with complete, selective, deficiency of C2, and normal serum chelated with Mg-EGTA. The C2-deficient serum killed promastigotes only after the addition of purified C2, and Mg-EGTA chelated serum had no detectable lethal effect. Thus, promastigotes appeared to activate C through the classical pathway. Human IgG and IgM, detected with 125I-anti-human antibody, bound to promastigotes. Removal of antibody from serum by absorption with promastigotes eliminated the lethal effect. The effect was restored by addition of heat-inactivated serum to absorbed serum. We conclude that promastigotes bind antibody and are killed by activation of the membrane attack complex of C through the classical pathway.

Animals↗
PubMed1998

Accommodation and T-independent B cell tolerance in rats with long term surviving hamster heart xenografts.

It was previously reported that treatment with leflunomide (LF; 10 mg/kg/day) together with cyclosporine (CsA; 10 mg/kg/day) resulted in long term survival of hamster heart xenografts (Xg) in rats and that LF could be withdrawn 2 to 4 wk after transplantation. To study the mechanisms allowing withdrawal of LF, second hamster heart Xgs were transplanted 6 wk after the first xenograft. Only the rats that received LF for 4 wk accepted second Xgs (>30 days; n = 5). Hence, after 4 wk of LF, the rats developed partial B cell tolerance, as they were unable to produce T-independent (CsA-resistant) XAbs. Rejection of second Xgs (2-4 days; n = 5) in the 2-wk LF group resulted in the formation of IgM xenoantibodies (XAbs) localizing together with complement within rejected grafts. However, these XAbs did not affect first Xgs, suggesting that the latter Xgs became resistant to this IgM XAb-mediated rejection, a phenomenon referred to as accommodation. Accommodation was further confirmed as adoptive transfer of IgM XAbs, which resulted in hyperacute Xg rejection in naive rats (<1 h; n = 5), did not cause rejection in long term survivors (>30 days; n = 4). This was associated with a down-regulation of the expression on the graft endothelial cells of adhesion molecules (believed to be important expressers of xenogeneic epitopes), such as P- and E-selectins. Interestingly, these adhesion molecules reappeared after retransplanting the accommodated Xgs to naive recipients. In conclusion, depending on the duration of the LF treatment, long term survival of hamster hearts in CsA-treated rats is based in part on accommodation and in part on T-independent B cell tolerance.

Adoptive Transfer↗