Influence of the donors' clinical status on in vitro and in vivo tumor-cytotoxic activation of interleukin-2-exposed lymphocytes and their circulation in different organs.
In-vitro-generated lymphokine-activated killer (LAK) cells of BALB/c mice, bearing the syngeneic colon carcinoma C-26 for 7 days, were as efficient as those from normal mice in lysing C-26 cells whereas LAK cells from 14-day tumor-bearing and 5- and 14-day tumor-resected animals had a lower C-26 cytotoxicity. The level of C-26 lysis returned to normal values 30 days after surgery. To identify the best source of LAK cells in vivo, groups of normal mice were treated with 10(4), 3 x 10(4) or 10(5) U/day of interleukin 2 (EL-2) for 7 days intraperitoneally (i.p.) or intravenously (i.v.) (3 x 10(4) dose only). The highest lysis on C-26 was obtained from peritoneal exudate cells of mice given 3 x 10(4) and 10(5) U whereas spleen cells were lytic only when taken from mice treated with 10(5) U IL-2. Peripheral blood lymphocytes lacked any cytotoxicity except for the group of mice which received IL-2 i.v. The kinetics of in vivo LAK activation in different organs showed a peak of anti-(C-26) lytic activity at day 5 in peritoneal exudate cells and spleen cells of mice given IL-2 for 5 days whereas administration of LAK cells alone had no effect: IL-2 plus LAK cells gave a lower peak of LAK activity as compared with IL-2 alone. A lower level of in vivo LAK activation was found in mice whose tumor was resected 5 days before; such impairment was evident even 14 days after surgery. Homing experiments were carried out with i.v. injected 51Cr-labelled LAK cells in normal or tumor-resected mice. In normal mice the highest radioactivity at 30 min was found in the lungs; liver and spleen also showed high radioactivity whereas blood had a negligible amount of radioactivity. Radioactivity declined rapidly in lungs (less than 10% after 24 h) while remaining at appreciable levels in the liver after 24 h and 48 h; spleen showed constant levels of 12%-15%. Homing of LAK cells was altered in mice receiving IL-2 i.p. for 5 days with slower and lower radioactivity peaks in the lung and higher levels in liver. In tumor-excised mice lower levels of radioactivity were found in lungs. These results show that: (a) alterations in LAK activity occur in early-tumor-resected and large-tumor-bearing animals; (b) the route of IL-2 administration is critical in LAK activation in vivo; (c) treatment with IL-2 modifies LAK homing.
Division of Experimental Oncology D, Istituto Nazionale Tumori, Milan, Italy.
M
M
Rodolfo
C
C
Salvi
G
G
Parmiani
D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000276:immunology / Q000601:surgery; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D005260:Female; D007116:Immunization, Passive; D007376:Interleukin-2; D007694:Killer Cells, Natural / Q000276:immunology* / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000601:surgery
D007376:Interleukin-2