Cancer-induced expansion and activation of CD11b+ Gr-1+ cells predispose mice to adenoviral-triggered anaphylactoid-type reactions.
Intravascular delivery (1.5 x 10(9) particles and higher) of recombinant adenovirus (rAd) induces myeloid cell mediated, self-limiting hemodynamic responses in normal mice. However, we observed anaphylactoid-type reactions and exacerbated hemodynamic events following rAd injection in mice bearing malignant 4T1 mammary carcinoma. Because 4T1 tumors induce significant CD11b(+)Gr-1(+) myeloid cell expansion and activation, we set to determine whether this causes rAd-induced exaggerated responses. When treated with a single intravenous dose (1 x 10(10) particles) of rAd, mice implanted with 4T1 carcinoma succumbed due to the anaphylactoid-type reactions. In contrast, normal mice and mice implanted with a related mammary carcinoma (66cl4) that does not induce CD11b(+)Gr-1(+) cell expansion, showed minimal responses. Depletion of phagocytic CD11b(+)Gr-1(+) cells prior to rAd delivery protected 4T1 tumor-bearing animals, whereas passive transfer of CD11b(+)Gr-1(+) cells from 4T1 tumor-bearing animals was sufficient to convey susceptibility to anaphylactoid-type reactions in normal animals. We further show that there is upregulation of nitric oxide and leukotriene signaling pathways in the 4T1 tumor-induced CD11b(+)Gr-1(+) myeloid cells and that pretreating mice with inhibitors of nitric oxide synthetase and leukotrienes can attenuate the anaphylactoid-type reactions. These data show that malignant tumor growth can alter CD11b(+)Gr-1(+) myeloid cells, rendering hosts susceptible to anaphylactoid-type reactions upon intravascular treatment with rAd.
Pande
Kalyan
K
Department of Immunology, Schering-Plough Biopharma, Palo Alto, California, USA.
Ueda
Roanna
R
Machemer
Todd
T
Sathe
Manjiri
M
Tsai
Van
V
Brin
Elena
E
Delano
Matthew J
MJ
Van Rooijen
Nico
N
McClanahan
Terrill K
TK
Talmadge
James E
JE
Moldawer
Lyle L
LL
Phillips
Joseph H
JH
LaFace
Drake M
DM
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000707:Anaphylaxis / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D039481:CD11b Antigen / Q000276:immunology*; D002319:Cardiovascular System / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004198:Disease Susceptibility; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects*; D006339:Heart Rate; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology; D008081:Liposomes; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010586:Phagocytes; D019707:Receptors, Chemokine / Q000276:immunology / Q000378:metabolism*; D018077:Receptors, Leukotriene / Q000378:metabolism
D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; D020024:Leukotriene Antagonists; D008081:Liposomes; D019707:Receptors, Chemokine; D018077:Receptors, Leukotriene; D019001:Nitric Oxide Synthase