Development of hyporesponsiveness of natural killer cells to augmentation of activity after multiple treatments with biological response modifiers

Abstract

Four biological response modifiers (BRMs), MVE-2 (maleic anhydride divinyl ether), Corynebacterium parvum (C. Parvum), PolyICLC (polyinosinic:polycytidylic acid stabilized with poly-L-lysine), and mouse alpha beta-interferon (alpha beta-IFN), were tested to assess whether repeated treatments would repeatedly induce or sustain augmented levels of natural killer (NK) cell activity and/or macrophage (M0)-mediated inhibition of tumor cell growth. In contrast to a significant increase in splenic NK activity obtained with a single treatment with each of the agents, multiple treatments with these BRMs led to a progressive decrease in the degree of augmentation of NK activity. In contrast, multiple injections with these agents resulted in sustained augmentation of M0-mediated reactivity. Separation of the spleen cells by Percoll discontinuous density gradient centrifugation indicated that with mice treated once with each BRM high levels of NK activity were detected in the lower density fractions and that these fractions contained a higher percentage of large granular lymphocytes (LGLs) than that found in comparable fractions from normal mice. In contrast, cells in the lower density fractions from mice that received multiple treatments had decreased NK activity and an appreciably lower proportion of LGLs. These results indicate that the development of hyporesponsiveness to augmentation of splenic NK-cell activity following multiple treatments with BRMs may be attributable to a decreased percentage of LGLs, the effector cell population responsible for NK cell-mediated cytotoxicity.

Virus-Induced Transient Immune Suppression and the Inhibition of T Cell Proliferation by Type I Interferon

“…2C). In contrast, antigen-mediated activation of CD8 T cells at the onset of virus infection, either involving HY cell transfer immediately prior to the time of LCMV infection or GP [33][34][35][36][37][38][39][40][41][42][43][44][45] inoculation immediately prior to the time of PV infection, markedly enhanced the proliferation of the bystander CD8 T cells (note differences in y axes) (Fig. 2D).…”

“…As shown in Fig. 3A, P14 CD8 T cells activated by GP [33][34][35][36][37][38][39][40][41][42][43][44][45] in naïve mice started to divide approximately 48 h after peptide treatment, and by 120 h, many of the P14 CD8 T cells in the naïve mice had fully diluted the CFSE. In contrast, only 23% Ϯ 8% (n ϭ 12) of the P14 CD8 T cells activated during the acute PV infection had divided at least once by 72 h after peptide treatment, compared to 87% Ϯ 6.4% (n ϭ 10) of P14 CD8 T cells activated in naïve mice at the same 72-h time point.…”

“…The division index for P14 CD8 T cells activated by GP [33][34][35][36][37][38][39][40][41][42][43][44][45] peptide in naïve mice peaked at 72 h after peptide treatment, while it was still increasing at 120 h for the P14 CD8 T cells activated in PV-infected mice (Fig. 3B).…”

“…with 5 ϫ 10 4 PFU of LCMV or 1.5 ϫ 10 7 PFU of PV. To activate P14 TCR-transgenic CD8 T cells in vivo, mice were inoculated with 5 g of a 13-mer peptide of the LCMV glycoprotein from amino acids 33 to 45 (GP [33][34][35][36][37][38][39][40][41][42][43][44][45] ) (KAVYNFATCGIFA), which is more effective than the minimal epitope (GP [33][34][35][36][37][38][39][40][41] ) for T cell activation in vivo (KAVYNFATC) (6). Alternatively, mice were inoculated with 10 7 GP 33-41 -labeled DC2.4 cells intravenously (i.v.).…”

“…Both peptides were purchased from 21st Century Biochemicals (Marlborough, MA). DC2.4 cells were incubated with 1 M GP [33][34][35][36][37][38][39][40][41] for 45 min at 37°C and washed 4 times in Hanks balanced salt solution (HBSS) to label. To block TNF, mice were inoculated with 100 g etanercept (Enbrel) i.p.…”