Abstract
Peripheral blood mononuclear cells (PBMCs) were obtained from patients receiving radioactive murine monoclonal antibody (MAb) therapy for malignant epithelial tumours, as well as normal controls, and were tested for the ability of T cells to proliferate in vitro in the presence of the MAb administered for therapy (HMFG1), and another isotypically matched antibody of irrelevant specificity (11.4.1). We studied 13 patients who had one (ten patients) or two (three patients) courses of MAB treatment, 11 age matched patients with the same histologic types of tumours, that had not received MAbs, and four normal controls. There was a consistent dose dependent in vitro T cell proliferation in 11 of the 13 patients after MAb therapy. This was not observed in the pre-therapy group of patients or normal controls, where the T cell proliferative responses remained baseline. The mean stimulation index (S.I.) in the post-therapy group was significantly higher than that of the pre-therapy patients and that of normal controls. When the in vitro T cell proliferative responses of these patients were measured in the presence of HMGF1 MAb (IgG1) and an isotypically identical, but idiotypically unrelated 11.4.1 MAb (IgG1), there was no statistically significant difference in the mean S.I. For HMFG1 vs 11.4.1 for the whole group of treated patients. When patients were separated into those who received one and those who received two MAb treatments, a significant increase in the mean S.I. was observed in the presence of HMFG1, in the group of patients receiving two treatment courses, suggesting the generation of T cells with specificity for the idiotypic component of the administered murine immunoglobulin. In order to further characterise these in vitro cellular responses we incubated PBMCs with and without an optimal concentration of the MAb (100-300 micrograms ml-1), as defined by the proliferation assay, and compared the differences in cell subpopulations. A significant increase in the percentage of cells expressing interleukin-2 receptors (IL-2R) was observed after MAb stimulation. The percentage of CD4+ lymphocytes and the CD4/CD8 ratio increased in all the cases studied, after MAb stimulation, where the percentages of B cells and NK cells remained relatively constant at less than 2-3% of the total population. We therefore conclude that murine MAbs administered to patients with cancer can lead to the generation of T cells which can recognise these MAbs as antigens when presented appropriately in vitro. The main proliferating population appears to be T helper CD4+ lymphocytes which following stimulation can release interleukin-2 leading to the expression of high levels of IL-2R.
Highlights
We studied 13 patients who had one or two courses of MAB treatment, 11 age matched patients with the same histologic types of tumours, that had not received monoclonal antibody (MAb), and four normal controls
T cell proliferation assays by 3H thymidine incorporation Eleven out of 13 patients receiving murine MAb therapy demonstrated an elevated T cell proliferation after in vitro stimulation with the MAb (HMFGI and 11.4.1) in a dose dependent manner
As mentioned in Methods, in some experiments the T cells were separated from the whole Peripheral blood mononuclear cells (PBMCs) population by negative selection, in order to exclude the possibility that the MAb, in vitro, might stimulate other populations such as B lymphocytes or monocytes
Summary
We studied 13 patients who had one (ten patients) or two (three patients) courses of MAB treatment, 11 age matched patients with the same histologic types of tumours, that had not received MAbs, and four normal controls. There was a consistent dose dependent in vitro T cell proliferation in 11 of the 13 patients after MAb therapy This was not observed in the pre-therapy group of patients or normal controls, where the T cell proliferative responses remained baseline. When the in vitro T cell proliferative responses of these patients were measured in the presence of HMGF1 MAb (IgGI) and an isotypically identical, but idiotypically unrelated 11.4.1 MAb (IgGI), there was no statistically significant difference in the mean S.I. For HMFGI vs 11.4.1 for the whole group of treated patients. When patients were separated into those who received one and those who received two MAb treatments, a significant increase in the mean S.I. was observed in the presence of HMFGI, in the group of patients receiving two treatment courses, suggesting the generation of T cells with specificity for the idiotypic component of the administered murine immunoglobulin
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