Protective immunity to nematode infection is induced by CTLA-4 blockade - PubMed (original) (raw)

Protective immunity to nematode infection is induced by CTLA-4 blockade

K McCoy et al. J Exp Med. 1997.

Abstract

The recent observation that neutralization or genetic deletion of the T lymphocyte receptor CTLA-4 allows enhanced T cell reactivity offers new opportunities for immunotherapy against infectious agents. We used a neutralizing antibody to block CTLA-4 interaction with its ligands CD80 and CD86 during infection of mice with the nematode, Nippostrongylus brasiliensis. CTLA-4 blockade greatly enhanced and accelerated the T cell immune response to N. brasiliensis, resulting in a profound reduction in adult worm numbers and early termination of parasite egg production. The ability of CTLA-4 blockade to accelerate primary immune responses to a protective level during an acute infection indicates its potential as an immunotherapeutic tool for dealing with infectious agents.

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Figures

Figure 1

Figure 1

Treatment with anti–CTLA-4 greatly enhances IL-5 production in lymph nodes draining the sites of infection with Nb. C57BL/6 mice were inoculated i.p. with 1,000 Nb L3 larvae and treated with control hamster IgG (open squares) or hamster anti–mouse CTLA-4 mAb (filled squares) at 1 mg/week beginning at day 0. Total lymph node cells were stimulated in vitro with anti-CD3 and IL-5 levels in the supernatant measured by ELISA. Values represent the mean concentration of IL-5 produced from 1 × 106 cells from 4 mice and adjusted to IL-5 production per lymph node based on the total lymph node cell number. Results shown are representative of three separate experiments. (A) IL-5 production from the draining mediastinal lymph node. (B) IL-5 production from the draining mesenteric lymph node. (C) IL-5 production from the inguinal lymph node. This lymph node does not drain any site of Nb infection.

Figure 2

Figure 2

Treatment with anti–CTLA-4 greatly enhances IL-4 production in lymph nodes draining the sites of infection with Nb. C57BL/6 mice were inoculated i.p. with 1,000 Nb L3 larvae and treated with control hamster IgG (open squares) or hamster anti–mouse CTLA-4 mAb (filled squares) as in Fig. 1. Total lymph node cells were stimulated in vitro as described in Fig. 1 and IL-4 levels in the supernatant measured by ELISA. Values represent the mean concentration of IL-4 produced from 1 × 106 cells from four mice and adjusted to IL-4 production per lymph node based on the total lymph node cell number. Results shown are representative of three separate experiments. (A) IL-4 production from the draining mediastinal lymph node. (B) IL-4 production from the draining mesenteric lymph node. (C) IL-4 production from the inguinal lymph node. This lymph node does not drain any site of Nb infection.

Figure 3

Figure 3

Treatment with anti–CTLA-4 increases total lymphocyte numbers in mediastinal lymph nodes of Nb-infected mice. C57BL/6 mice were inoculated i.p. with 1,000 Nb L3 larvae and treated with control hamster IgG (open squares) or hamster anti–mouse CTLA-4 mAb (filled squares) as in Fig. 1. Values represent the mean cell number from four mice ± SE and results are representative of three separate experiments.

Figure 4

Figure 4

Treatment with anti–CTLA-4 decreases parasite egg output in a primary Nb infection and does not affect development of memory to a subsequent infection with Nb. (A) C57BL/6 mice were inoculated i.p. with 1,000 L3 Nb larvae and left untreated (open squares) or treated with anti–CTLA-4 neutralizing mAb (filled squares) as described in Fig. 1. Feces were collected daily from groups of mice (n = 8) starting day 6 after infection. (B) Mice from A were inoculated i.p. with 1,000 L3 Nb larvae 68 d after primary Nb infection. During the primary infection mice were untreated (open squares) or treated with anti–CTLA-4 mAb (filled squares) as above. The last injection of mAb was given 21 d after primary infection. Feces were collected daily from groups of mice (n = 8) starting day 5 after challenge.

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