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

McCoy K, Camberis M, Gros GL - J. Exp. Med. (1997)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Malaghan Institute for Medical Research, Wellington School of Medicine, Wellington, New Zealand.

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.

Show MeSH

Related in: MedlinePlus

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.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2198990&req=5

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.

Mentions: To establish whether T cell effector function is altered by blockade of CTLA-4 signaling, we followed IL-4 and IL-5 production in the draining mediastinal and mesenteric lymph nodes of mice infected with Nb and receiving weekly injections of anti–CTLA-4 neutralizing mAb. We found that anti–CTLA-4 mAb treatment induced a profound 20-fold increase in IL-5 production (Fig. 1 a) and a massive 40-fold increase in IL-4 production (Fig. 2 a) from the draining mediastinal lymph node at day 6 after infection compared to mice given control antibody. Significantly, the peak mediastinal cytokine production of both IL-5 and IL-4 during CTLA-4 blockade occurred earlier than that in control mice. Increased cytokine production in response to CTLA-4 blockade was due to increased lymphocyte numbers per mediastinal lymph node as well as increased cytokine production. The mediastinal lymph node obtained from mice given anti–CTLA-4 mAb had nearly fourfold more lymphocytes 6 d after infection than control mice (Fig. 3). Cytokine production in mesenteric lymph nodes was also significantly increased with anti–CTLA-4 mAb treatment (IL-5; Fig. 1 b, IL-4; Fig. 2 b) but it is interesting that in this lymph node peak cytokine production occurred at the same time in control and anti–CTLA-4– treated mice. Increased cytokine production from this lymph node reflected increased IL-4 and IL-5 production only as total mesenteric lymph node cell numbers were not significantly different between groups (data not shown). The observation that increased cellularity and cytokine production only occurred in the lymph nodes draining the site of infection and not the inguinal nodes indicated that the effect of CTLA-4 blockade was antigen driven (IL-5; Fig. 1 c, IL-4; Fig. 2 c).


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

McCoy K, Camberis M, Gros GL - J. Exp. Med. (1997)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198990&req=5

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.
Mentions: To establish whether T cell effector function is altered by blockade of CTLA-4 signaling, we followed IL-4 and IL-5 production in the draining mediastinal and mesenteric lymph nodes of mice infected with Nb and receiving weekly injections of anti–CTLA-4 neutralizing mAb. We found that anti–CTLA-4 mAb treatment induced a profound 20-fold increase in IL-5 production (Fig. 1 a) and a massive 40-fold increase in IL-4 production (Fig. 2 a) from the draining mediastinal lymph node at day 6 after infection compared to mice given control antibody. Significantly, the peak mediastinal cytokine production of both IL-5 and IL-4 during CTLA-4 blockade occurred earlier than that in control mice. Increased cytokine production in response to CTLA-4 blockade was due to increased lymphocyte numbers per mediastinal lymph node as well as increased cytokine production. The mediastinal lymph node obtained from mice given anti–CTLA-4 mAb had nearly fourfold more lymphocytes 6 d after infection than control mice (Fig. 3). Cytokine production in mesenteric lymph nodes was also significantly increased with anti–CTLA-4 mAb treatment (IL-5; Fig. 1 b, IL-4; Fig. 2 b) but it is interesting that in this lymph node peak cytokine production occurred at the same time in control and anti–CTLA-4– treated mice. Increased cytokine production from this lymph node reflected increased IL-4 and IL-5 production only as total mesenteric lymph node cell numbers were not significantly different between groups (data not shown). The observation that increased cellularity and cytokine production only occurred in the lymph nodes draining the site of infection and not the inguinal nodes indicated that the effect of CTLA-4 blockade was antigen driven (IL-5; Fig. 1 c, IL-4; Fig. 2 c).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Malaghan Institute for Medical Research, Wellington School of Medicine, Wellington, New Zealand.

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.

Show MeSH
Related in: MedlinePlus