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PubMed1996

No advantage of flow cytometry crossmatch over complement-dependent cytotoxicity in immunologically well-documented renal allograft recipients.

The effect of flow cytometry crossmatches on clinical outcome was studied retrospectively in two groups of immunologically well-documented patients who had received transplants with a negative complement-dependent cytotoxicity crossmatch. The first group consisted of 114 consecutive renal allograft recipients, and the second group consisted of 76 immunologically at-risk recipients. Flow cytometry crossmatches were performed with current and historic sera. In group 1, positive flow cytometry (FC) crossmatches were shown in 15/114 (13%) recipients. Rejection occurred in 8/15 (53%) FC-positive versus 41/99 (41%) FC-negative recipients. The 1-year graft survival rate was 80% for FC-positive patients and 87% for FC-negative patients. Sixty-seven patients were nonsensitized patients; 4 of them had a positive FC crossmatch but no rejection episodes, graft loss, or patient loss. Of 47 retransplanted and/or sensitized recipients, 11 had a positive FC crossmatch. Rejection treatment was needed in 8/11 (73%) FC-positive patients compared with 19/36 (53%) FC-negative patients. Their 1-year graft survival rates were 73% and 81%. None of these differences reached statistical significance. Group 2 consisted of 76 at-risk recipients; 37 were retransplant patients and 39 were sensitized first-transplant patients. Twenty-one (28%) patients showed a positive FC crossmatch. Rejection episodes did not differ between the FC-positive (48%) and FC-negative patients (46%). There was no difference in 1-year graft survival rate (76% vs. 80%) or in 1-year patient survival rate (100% vs. 95%). We conclude that FC crossmatches in our patient group are not superior to the classical complement-dependent cytotoxicity crossmatches with regard to clinical outcome. On the contrary, transplantation with a mandatory negative FC crossmatch would have excluded 28% of the recipients from transplantation, who in fact are doing well.

Adult↗
PubMed1997

Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus.

This study was performed to test the hypothesis that cytotoxic T lymphocyte (CTL) selection of hepatitis C virus (HCV) escape variants plays a role in HCV persistence. The peripheral blood CTL responsiveness of patients with well-established chronic hepatitis C to a panel of 10 prototype HCV peptides (genotype 1a) was compared with the corresponding sequences encoded by the infecting viruses in each patient. Variant viral peptide sequences were threefold more frequent in the presence of a CTL response than in its absence, and CTL responses were detected nearly twice as often in association with variant rather than with prototype viral peptide sequences. Furthermore, over half of the patients were infected with potential CTL escape variants that contained nonimmunogenic and noncross-reactive variant peptides many of which displayed reduced HLA-binding affinity. Surprisingly, follow up analysis over a period of up to 46 mo revealed that, in contrast to the relatively high frequency of escape variants initially observed, the subsequent emergence rate of CTL escape variants was very low. Interestingly, the one escape variant that was detected proved to be a CTL antagonist. Collectively, these observations suggest that CTL selection of epitope variants may have occurred in these patients before their entrance into the study and that it may have played a role in HCV persistence. The low apparent rate of ongoing CTL selection in chronically infected patients, however, suggests that if CTL escape occurs during HCV infection it is probably an early event.

Adult↗
PubMed1980

Antibody-mediated complement-dependent cytotoxicity in immunologically induced experimental colon disease.

Rabbits immunized with a saline extract of intestinal tissue in complete Freund's adjuvant produce antibody which mediates complement-dependent cytotoxicity for colon epithelial cells in vitro. The presence of this antibody did not correlate with histologic alterations of the colon in the immunized rabbits. This suggests that antibody-mediated complement-dependent cytotoxicity may not be a factor in the pathogenesis of experimentally induced immunologically mediated colon disease.

Animals↗
PubMed2001

Mac-1 (CD11b/CD18) is essential for Fc receptor-mediated neutrophil cytotoxicity and immunologic synapse formation.

Receptors for human immunoglobulin (Ig)G and IgA initiate potent cytolysis of antibody (Ab)-coated targets by polymorphonuclear leukocytes (PMNs). Mac-1 (complement receptor type 3, CD11b/CD18) has previously been implicated in receptor cooperation with Fc receptors (FcRs). The role of Mac-1 in FcR-mediated lysis of tumor cells was characterized by studying normal human PMNs, Mac-1-deficient mouse PMNs, and mouse PMNs transgenic for human FcR. All PMNs efficiently phagocytosed Ab-coated particles. However, antibody-dependent cellular cytotoxicity (ADCC) was abrogated in Mac-1(-/-) PMNs and in human PMNs blocked with anti-Mac-1 monoclonal Ab (mAb). Mac-1(-/-) PMNs were unable to spread on Ab-opsonized target cells and other Ab-coated surfaces. Confocal laser scanning and electron microscopy revealed a striking difference in immunologic synapse formation between Mac-1(-/-) and wild-type PMNs. Also, respiratory burst activity could be measured outside membrane-enclosed compartments by using Mac-1(-/-) PMNs bound to Ab-coated tumor cells, in contrast to wild-type PMNs. In summary, these data document an absolute requirement of Mac-1 for FcR-mediated PMN cytotoxicity toward tumor targets. Mac-1(-/-) PMNs exhibit defective spreading on Ab-coated targets, impaired formation of immunologic synapses, and absent tumor cytolysis.

Animals↗
PubMed1982

Immunoselection of tumor variants resistant to antibody-mediated cytotoxicity. Their immunologic and metastatic characterization.

The immunological characteristics of two series of metastatic variants of restricted genetic origin were related to their lung-colony-forming potential. A series of metastatic variants was isolated from a tumor-cell population in which heterogeneity appeared following short-term in vivo passage, while a second series of variants were immunoselected in vitro for resistance to antibody-complement-mediated cell lysis. In the case of the first series, the sensitivity of the individual variants to cell-mediated and antibody-complement-mediated cytotoxicity appeared to be partly determined by the number and rate of loss of antibody-binding sites on the cell surface. These characteristics also correlated with the efficiency of experimental metastasis in the animal. We compared the results reported herein with our previous studies of nonimmune parameters for this series of metastatic variants, and we conclude that immunological differences can be important to the efficiency of lung-colony formation. However, in the case of the second series of variants, despite selection in vitro for resistance to antibody-complement-mediated cell lysis, the behavior of these variants in the lung colony assay could not be predicted by the immunologic parameters examined.

Animals↗
PubMed2002

C6-like and C3-like molecules from the cephalochordate, amphioxus, suggest a cytolytic complement system in invertebrates.

The mammalian immune system has cytotoxic mechanisms, both cellular and humoral, that destroy the membrane integrity of target cells. The main effector molecules of these cytolytic mechanisms-perforin, used by killer lymphocytes, and the membrane attack complex (MAC) components of the complement system-share a unique module called the MAC/perforin module. Until now, both immunological cytotoxicity and the MAC/perforin module have been reported only in jawed vertebrates. Here, we report the identification of a protein containing the MAC/perforin module from the invertebrate cephalochordate, amphioxus ( Branchiostoma belcheri), using expressed sequence tag (EST) analysis of the notochord. The deduced amino acid sequence of this molecule is most similar to the primary structure of human complement component C6 and is designated AmphiC6. AmphiC6 shares a unique modular structure, including the MAC/perforin module, with human C6 and other MAC components. Another EST clone predicts the presence of a thioester-containing protein with the closest structural similarity to vertebrate C3 (therefore designated AmphiC3). AmphiC3 retains most of the functionally important residues of vertebrate C3 and is shown by phylogenetic analysis to be derived directly from the common ancestor of vertebrate C3, C4, and C5. Only opsonic activity has been assigned to the invertebrate complement system until now. Therefore, this is the first molecular evidence for complement-mediated immunological cytotoxicity in invertebrates.

Amino Acid Sequence↗
PubMed1993

Studies of the synthesis, immunology, and cytotoxicity of a cyclic octapeptide corresponding to TNF-alpha-(59-66).

In an attempt to investigate possible binding domains of the tumor necrosis factors (TNF), we have previously synthesized a cyclic hexapeptide corresponding to murine TNF-(127-132) (cTNF-1). In this report, we describe the synthesis and biological activity of another cyclic octapeptide corresponding to human TNF-alpha-(59-66) (cTNF-2). The design of these cyclic peptides is based on their high sequence homology with corresponding fragments of human TNF-alpha or TNF-beta. Similar to cTNF-1, the cyclic octapeptide cTNF-2 displayed low in vitro cytotoxicity against human HeLa and HEP-2 cell lines. The cyclic peptides cTNF-2 and cTNF-1 were then tested for the induction of interleukin-1 (IL-1) production from human peripheral blood mononuclear cells and monocytes in vitro. At low concentrations, the IL-1 levels induced by these cyclic peptides were similar to that of recombinant TNF-alpha. However, the IL-1 production by cTNF-2 stimulation was dose-dependently increased and reached that of a lipopolysaccharide (LPS; 0.1 micrograms/mL) level. These findings suggest that the fragments corresponding to human TNF-alpha-(59-66) and murine TNF-(127-132) may represent certain binding domains of the tumor necrosis factors that elicit IL-1 production.

Amino Acid Sequence↗
PubMed1990

Cytotoxic and immunologic effects of methotrexate in psoriasis.

Based on recent experience that Cyclosporin A, an immunosuppressive drug, produces marked improvement in psoriasis, possible immunomodulatory activities of methotrexate (MTX) have been reviewed to look for alternate mechanisms of MTX action in psoriasis. It is generally considered that the therapeutic results of MTX in psoriasis are related to a direct effect on epidermal cell hyperplasia through inhibition of DNA synthesis. Several studies in the literature now suggest possible effects of MTX on the immune system of psoriatics as well as in animal models that may have some pathogenic similarities to psoriasis. In psoriatics receiving MTX, neutrophil chemotaxis is suppressed, resulting in a possible alteration in the potential pathologic activity of neutrophils commonly found in lesional skin. MTX does improve both psoriatic and rheumatoid arthritis. Animal studies of the latter using adjuvant arthritis and graft vs host disease (GVHD) have indicated several possible mechanisms for MTX that affect these processes. In GVHD, MTX selectively destroys cycling CD8+ cells, and in adjuvant arthritis the activation of macrophages is prevented by inhibition of T-cell function. While MTX generally has not been clinically utilized as an immunomodulatory drug for immunologically related diseases, it may, nonetheless, have selective actions that could be specific for some diseases. MTX and Cyclosporin A could work mechanistically in similar ways but at different steps in the activation of T cells and macrophages. It may be that the major direct effect of MTX on epidermal cell proliferation is complemented or even mediated by subtle immunoregulatory effects on the melange of cells in the affected skin and the systemic immune response.

Animals↗
PubMed1991

Immunologically mediated cytotoxicity against human eye muscle and thyroid cells in euthyroid and thyrotoxic Graves' ophthalmopathy.

We have studied the role of eye muscle and thyroid autoimmunity in patients with Graves' hyperthyroidism with or without ophthalmopathy in an area of relatively low iodine intake. Antibody dependent cell mediated cytotoxicity (ADCC) and complement mediated antibody dependent cytotoxicity (CMAC) against thyroid and eye muscle cells, and levels of antibodies against TSH receptor antigen and the thyroid microsomal antigen (thyroid peroxidase) were determined in three groups of patients: (1) thyrotoxic with exophthalmos (TX, n = 28), (2) thyrotoxic without ophthalmopathy (GR, n = 10), and (3) euthyroid ophthalmopathy (EU, n = 12). The thyroid glandular mass of the EU group was significantly less (P less than 0.01) compared with TX or GR. Mean (+/- SD) TSH receptor antibody (TRAb) level was 27 +/- 14% in EU which was significantly lower compared with TX (52.4 +/- 20%) and GR (59 +/- 18%). The prevalence of microsomal antibodies were similar and not significantly different in the three groups. On the other hand the prevalence of positive ADCC and CMAC tests was significantly greater, and at higher levels, in EU (ADCC THY CELLS 10.9 +/- 8.9% SL, ADCC Eye muscle = 25.9 +/- 20% SL, CMAC = 70.2 +/- 43% SL) and TX (ADCC THY CELLS = 9.3 +/- 9.2% SL, ADCC Eye muscle = 20.1 +/- 19% SL, CMAC = 62.4 +/- 30% SL) compared to GR (ADCC THY CELLS = 4.4 +/- 9.5% SL, ADCC Eye muscle = 7.7 +/- 6.7% SL, CMAC = 24.7 +/- 23% SL).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

[Effects of Phytolacca acinosa polysaccharides I on cytotoxicity of macrophages and its production of tumor necrosis factor and interleukin 1].

The in vivo effects of Phytolacca acinosa polysaccharides I (PEP-I) on immunologic cytotoxicity of mouse peritoneal macrophages and its production of tumor necrosis factor (TNF) and interleukin 1 (IL-1) were studied. PEP-I 80, 160 mg/kg was given ip twice every 4 d. Both doses were found to have significant enhancing activity on macrophages cytotoxicity against S180 sarcoma cells and malignant transformed fibroblast L929 cells. Peritoneal activated macrophages were incubated with LPS for 2 and 24 h to induce TNF and IL-1, respectively. The TNF and IL-1 activities were tested from cytotoxicity against L929 cells in an absorbance assay of enzymatic reaction and proliferation of thymocytes co-stimulated assay separately. The optimal time for TNF production was found on d 8. Significant increases in TNF and IL-1 were observed. In comparison of the effect of PEP-I on TNF with that of known priming agent BCG, there was no difference between these two, but PEP-I had a high effect on IL-1. These results suggest that cytotoxicity of macrophages primed by PEP-I is closely related to its TNF and IL-1 production.

Animals↗
PubMed1993

Modulation of the effect of humoral-mediated cytotoxicity on isolated rat pancreatic islets by glucose.

Rat islets of Langerhans exposed for 20 h at high glucose (20 mmol/l) to 50% or 20% experimentally raised rabbit anti-rat islet cell surface antiserum (ICSA-positive serum) plus complement exhibited an irreversible loss of glucose-stimulated insulin secretion. In contrast, islets treated with 50% ICSA-positive serum at low glucose (5.5 mmol/l) could overcome this alteration within a subsequent 48 h recovery period at 10 mmol/l glucose in the absence of ICSA, and islets affected at 5.5 mmol/l glucose by 20% ICSA-positive serum even retained the insulin secretory potential and responded on glucose challenge already immediately after the removal of ICSA. The islet insulin content was reduced by the effect of 50% as well as of 20% ICSA-positive serum and complement irrespective of whether the glucose level amounted to 5.5 or 20 mmol/l during serum influence. However, islets altered in a normoglycaemic environment at 5.5 mmol/l glucose by 20% ICSA-positive serum restored their insulin content up to the level of control islets, whereas those islets affected under hyperglycaemic conditions at 20 mmol/l glucose only partially recovered. Thus, beta-cell loss and/or impairment of the insulin secretory mechanisms result from the simultaneous action of humoral-mediated anti-islet cytotoxicity and elevated glucose level, and cause the diminished insulin secretory potential of the islets. These results support the hypothesis that decreasing the insulin secretory activity of beta cells may protect them from cytotoxic immunological attacks.

Animals↗
PubMed1983

Particular features of cell-mediated immunity in patients with anaplastic gliomas. A comparison with kidney and bladder cancer patients.

The authors studied 24 patients affected by anaplastic gliomas in regard to the killer (Antibody-Dependent Cellular Cytotoxicity) and natural killer (Spontaneous Lymphocyte-Mediated Cytotoxicity) immunological functions, by counting the Cr51 release in Change liver and K 562 cell cultures, respectively. These parameters were also evaluated in 24 healthy donors as control, in 24 patients affected by bladder cancer and in nine cases of kidney cancer. Our data show, pre-operatively, a statistically significant impairment of ADCC and SLMC activity in glioma patients as compared both with controls, bladder and kidney cancer patients. The particular impairment of K and NK functions in gliomas is discussed with regard to the specific features of Central Nervous System malignancies. An improvement of ADCC activity was also found in the post-operative samples. This finding confirms other reports about partial restoring of altered immunocompetence after surgery, suggesting a link between extention of tumor mass and impaired immunological reactions.

Adult↗
PubMed2001

Glial cells as targets for cytotoxic immune mediators.

Oligodendrocytes and Schwann cells are the glia principally responsible for the synthesis and maintenance of myelin. Damage may occur to these cells in a number of conditions, but perhaps the most studied are the idiopathic inflammatory demyelinating diseases, multiple sclerosis in the CNS, and Guillain-Barré syndrome and its variants in the peripheral nervous system (PNS). This article explores the effects on these cells of cytotoxic immunological and inflammatory mediators: similarities are revealed, of which perhaps the most important is the sensitivity of both Schwann cells and oligodendrocytes to many such agents. This area of research is, however, characterised and complicated by numerous and often very substantial inter-observer discrepancies. Marked variability in cell culture techniques, and in assays of cell damage and death, provide artifactual explanations for some of this variability; true inter-species differences also contribute. Not the least important conclusion centres on the limited capacity of in vitro studies to reveal disease mechanisms: cell culture findings merely illustrate possibilities which must then be tested ex vivo using human tissue samples affected by the relevant disease.

Animals↗
PubMed1980

An immunological suppressor cell inactivating cytotoxic T-lymphocyte precursor cells recognizing it.

The immune system does not normally react against self components. Originally, it was postulated that self-reactive cells were somehow deleted or blocked. More recent thinking is that such cells are suppressed by regulatory networks similar to those limiting the immune response against non-self determinants. Both mechanisms may exist. I describe here a type of suppression more closely related to the first postulate. In the in vitro, one-way, mixed lymphocyte reaction (MLR), cytotoxic T-lymphocyte precursor cells (CLP) from the responder population give rise to cytotoxic T-lymphocytes (CL) capable of lysing target cells from the stimulator population. A subpopulation of cells in the spleen of athymic nude mice can, when added to such cultures, inactivate CLP capable of recognizing either the H-2 antigens or TNP modifications of the nude spleen. Regarding the nude spleen cells, activation of self-reactive cells is being prevented.

Animals↗