The induction of bacillus-Calmette-Gu�rin-activated killer cells requires the presence of monocytes and T-helper type-1 cells

Abstract

Previously we have described the induction of MHC-unrestricted killer cells against bladder tumour cells by bacillus Calmette-Guérin (BCG), termed BCG-activated killer (BAK) cells. In the present paper we deal with the accessory-cell requirement for the activation of BAK cells. We show that monocytes are required for activating BAK cells, since no cytotoxicity can be induced in the absence of monocytes. Therefore, these phagocytes may represent the first step during the activation cascade of BAK cells. Furthermore, the presence of CD4+ T cells was essential for generating BAK cells: depleting peripheral blood mononuclear cells of CD4+ cells prior to stimulation with BCG abolished the cytotoxicity against bladder tumour cells. Experiments with monoclonal antibodies (mAb) neutralizing the activity of either interleukin-2 (IL-2) or interferon gamma (IFN gamma) underlined the importance of these cytokines: both mAb blocked the induction of BAK cells. Since both cytokines are related to the so-called Th1 pattern of T cells, we consider the second step of the generation of BAK cells as follows: monocytes presenting antigens of BCG trigger Th1-like cells in a preferred manner. These Th1-like T cells secrete IL-2 and IFN gamma and, thus, activate the BAK effector cells. Since CD4+ cells are dominant in the cells infiltrating the bladder wall after intravesical instillation of BCG in vivo, we postulate an important role for the Th1 subpopulation. We further postulate that the occurrence of macrophages in this infiltrate seems to be significant in the maintenance of the relapse-free state of the patient.

Humoral response against heat shock proteins and other mycobacterial antigens after intravesical treatment with bacille Calmette–Guérin (BCG) in patients with superficial bladder cancer

“…Intravesical BCG therapy has been demonstrated to be a very effective treatment in the prevention of superficial bladder tumour recurrences [1]. The BCG mode of action has been termed an immunotherapy since a cascade of immunological reactions has been described in relation to it [2][3][4][5][6]. Despite its well recognized efficacy, many questions about its precise mechanism of action remain unanswered.…”

Peritoneal tuberculosis and granulomatous hepatitis secondary to treatment of bladder cancer with Bacillus Calmette-Guérin

“…This infiltration leads to an increase in cytotoxic T-cells and macrophages. Thus, severe local inflammation causes local ischemia and the destruction of tumor cells [ 16 , 17 ]. Intravesical BCG administration causes common local side effects such as hematuria, cystitis, bladder contracture, granulomatous prostatitis, and renal abscess.…”

Zytotoxizität natürlicher Killerzellen gegen ex vivo isolierte autologe urotheliale Blasentumorzellen bei Patienten mit urothelialem Blasenkarzinom

“…Die Zielzellen wurden mit 20u,Ci L-[ 3 H]-Methionin für 4 Stunden in L-Methionin freiem Medium markiert. Nach Zugabe der Effektorzellen in einem Effektor-/Zielzellverhältnis (E/Z) von 40:1 erfolgte die Auswertung des Zytotoxizitätsassays wie bereits beschrieben (2,8).…”