RESUMEN
BACKGROUND: Transitional cell carcinoma (TCC) of the bladder is associated with alterations in the immune system of the host. The authors demonstrated that in patients with bladder carcinoma there is a negative correlation between the levels of natural killer (NK) activity and the clinical evolution and pathologic stages of disease. METHODS: The authors investigated the effect of various doses of recombinant interferon-alpha-2b (IFN-alpha-2b) for variable periods of culture on the nonmajor histocompatibility-restricted cytotoxic activity of peripheral blood mononuclear cells (PBMNC) with or without CD16 and CD3-depleted populations from patients with superficial (confined to the mucosa or lamina propria) and infiltrative (those infiltrating beyond the lamina propria) TCC of the bladder using 4-hour 51-sodium chromate (51Cr)-release cytotoxicity assays against both NK-sensitive (K562) and NK-resistant (JY) tumor target cells. RESULTS: The normal NK activity detected in PBMNC from patients with superficial TCC of the bladder can be significantly enhanced by short-term (18-hour) incubation with recombinant IFN-alpha (P < 0.05). The depressed NK cytotoxic activity found in PBMNC from patients with infiltrative TCC can also be significantly enhanced, but not normalized, by short-term (18-hour) incubation with recombinant IFN-alpha (P < 0.05). Short-term recombinant IFN-alpha-incubated PBMNC from patients with superficial, but not infiltrative, TCC of the bladder also showed marked cytotoxic activity against NK-resistant target cells. By selection with CD16 or CD3 monoclonal antibodies and complement, it was also found that the precursor and effector lymphocytes of this recombinant IFN-alpha-promoted cytotoxicity belong to NK lineage. In kinetic studies, it was found that the maximal levels of the recombinant IFN-alpha-promoted cytotoxic activity against NK-sensitive and NK-resistant target cells in PBMNC from patients with TCC were reached after 18 hours of culture. CONCLUSION: Recombinant IFN-alpha can enhance the nonmajor histocompatibility-restricted cytotoxic activity of PBMNC from patients with TCC of the bladder.
Asunto(s)
Carcinoma de Células Transicionales/inmunología , Interferón-alfa/farmacología , Células Asesinas Naturales/inmunología , Neoplasias de la Vejiga Urinaria/inmunología , Anciano , Carcinoma de Células Transicionales/sangre , Células Cultivadas , Citotoxicidad Inmunológica/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Activación de Linfocitos/inmunología , Masculino , Invasividad Neoplásica , Proteínas Recombinantes , Linfocitos T/inmunología , Factores de Tiempo , Neoplasias de la Vejiga Urinaria/sangreRESUMEN
We have investigated the effect of thymostimulin on the major histocompatibility (MHC) unrestricted cytotoxic activity of peripheral blood mononuclear cells (PBMNC) from patients with superficial transitional cell carcinoma (TCC) of the bladder. PBMNC from patients and healthy controls were incubated in the presence of thymostimulin for varying periods of time (2 or 18 h or 5 days), and were used as effectors against 51Cr-radiolabeled natural killer (NK)-sensitive (K-562) and NK-resistant (JY) target cells in cytotoxic assays. In 6 out of 14 patients analyzed, thymostimulin enhanced the cytotoxic activity of PBMNC against NK-sensitive target cells in a dose-dependent manner. This cytotoxic inducer effect of thymostimulin was maximal after 18 h of culture. Thymostimulin failed to induce lytic activity in PBMNC from TCC patients against NK-resistant target cells. We also found that thymostimulin could synergize with interleukin-2 in inducing non-MHC restricted cytotoxic activity in PBMNC from TCC patients. In conclusion, we have demonstrated that thymostimulin can enhance the natural killer cytotoxic activity of PBMNC from patients with TCC of the bladder.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Carcinoma de Células Transicionales/inmunología , Citotoxicidad Inmunológica/efectos de los fármacos , Células Asesinas Naturales/efectos de los fármacos , Extractos del Timo/farmacología , Neoplasias de la Vejiga Urinaria/inmunología , Anciano , Femenino , Humanos , Interleucina-2/farmacología , Células Asesinas Naturales/inmunología , MasculinoRESUMEN
Incubation of peripheral blood mononuclear cells (PBMNC) from patients with transitional cell carcinoma of the bladder, with interferon (IFN-alpha 2b) causes dose-dependent enhancement of natural killer (NK) and cytotoxic activity. Increased lytic activity was also observed against both NK-sensitive and NK-resistant target cells and T lymphocytes from such patients showed altered activity upon incubation with IFN-alpha 2b. Furthermore, intracavitary instillation of IFN-alpha 2b is associated with infiltration of the bladder wall by NK cells and T lymphocytes. Future work will be aimed at investigating the possible prognostic value of these results as related to the therapeutic effect of intracavitary instillation of IFN-alpha 2b.
Asunto(s)
Carcinoma de Células Transicionales/inmunología , Interferón-alfa/fisiología , Células Asesinas Naturales/fisiología , Linfocitos T/fisiología , Neoplasias de la Vejiga Urinaria/inmunología , Carcinoma de Células Transicionales/terapia , Humanos , Interferón-alfa/uso terapéutico , Neoplasias de la Vejiga Urinaria/terapiaRESUMEN
Following complete transurethral resection, patients with superficial transitional cell carcinoma (TCC) were treated with intravesical interferon-alpha 2b. Ex vivo analysis of peripheral blood mononuclear cells (PBMNC) both during and after the treatment period showed an enhancement of natural killer (NK) activity which fell to basal levels upon cessation of therapy. Simultaneous analysis of T-cell activity revealed a similar pattern of variation in the response to the polyclonal mitogen phytohemagglutinin. Both findings point to an alteration in systemic immunoreactivity as a result of intravesical treatment. Further work will be aimed at determining whether this is relevant to the therapeutic value of such treatment and whether prolonged treatment will maintain these effects.
Asunto(s)
Carcinoma de Células Transicionales/terapia , Interferón-alfa/uso terapéutico , Neoplasias de la Vejiga Urinaria/terapia , Administración Intravesical , Carcinoma de Células Transicionales/inmunología , Humanos , Células Asesinas Naturales/metabolismo , Estudios Prospectivos , Linfocitos T/metabolismo , Neoplasias de la Vejiga Urinaria/inmunologíaRESUMEN
It has been shown that natural killer (NK) cells are involved in the immunosurveillance of tumors. In patients with transitional cell carcinoma (TCC) of the bladder, there is a negative correlation between the levels of NK activity in peripheral blood mononuclear cells (PBMNCs) and both the clinical evolution and the pathological stages of the disease. We have investigated the immunoregulatory effect of keyhole limpet hemocyanin (KLH) on the NK activity of patients with TCC of the bladder. We found that KLH enhances the cytotoxic activity of PBMNC from patients with superficial TCC against NK-sensitive target cells in a time-dependent manner. This KLH-enhanced cytotoxicity is not directed against NK-resistant target cells. However, KLH fails to normalize the depressed NK activity of PBMNCs from patients with infiltrative TCC. The present in vitro studies suggest that this immunoregulatory effect of KLH on NK cytotoxicity may be implicated in its therapeutic effect on superficial TCC of the bladder.