PMID- 9922215
OWN - NLM
STAT- MEDLINE
DCOM- 19990311
LR  - 20031114
IS  - 1044-1549 (Print)
IS  - 1044-1549 (Linking)
VI  - 20
IP  - 2
DP  - 1999 Feb
TI  - Effects of chronic anti-interleukin-5 monoclonal antibody treatment in a murine 
      model of pulmonary inflammation.
PG  - 248-55
AB  - The maturation of eosinophils in bone marrow, their migration to pulmonary 
      tissue, and their subsequent degranulation and release of toxic granule proteins 
      contributes to the pathophysiology observed in asthma. Interleukin-5 (IL-5) is 
      essential for these processes to occur. Therefore, much emphasis has been placed 
      on attempts to inhibit the production or activity of IL-5 in order to attenuate 
      the inflammatory aspect of asthma. In this report, the immunological consequences 
      of long-term exposure to an antibody recognizing IL-5 (TRFK-5) were studied in a 
      murine pulmonary inflammation model. A single dose of TRFK-5 (1 mg/ kg, 
      intraperitoneally) reversibly inhibited antigen-dependent lung eosinophilia in 
      mice for at least 12 wk and inhibited the release of eosinophils from bone marrow 
      for at least 8 wk. Normal responses to aerosol challenge were attained after 24 
      wk. In mice treated acutely with antibody (2 h before challenge), 50% inhibition 
      of pulmonary eosinophilia occurred when 0. 06 mg/kg TRFK-5 was administered 
      (intraperitoneally; ED50), resulting in 230 ng/ml (IC50) in serum. In mice 
      treated with one dose of TRFK-5 (1 mg/kg) and rested before challenge, the 
      antibody exhibited a half-life of 2.4 wk. After 18 to 19 wk, antigen 
      challenge-induced eosinophilia was inhibited by 50% and serum levels of TRFK-5 
      were 25 ng/ml. TRFK-5 remaining in mice 8 wk after a single injection of TRFK-5 
      was sufficient to inhibit at least 50% of the eosinophilia induced in blood 3 h 
      after injection of recombinant murine IL-5 (10 microg/kg, intravenously). To 
      assess the biologic effect of long-term exposure of mice to antibody, several 
      parameters of immune-cell function were measured. Throughout the extended period 
      of activity of TRFK-5 (>/= 12 wk) there were no gross effects on 
      antigen-dependent increases in T-cell recruitment into bronchoalveolar fluid 
      (BALF), in IL-4 and IL-5 steady-state mRNA levels in lung tissue, or in 
      immunoglobulin E (IgE) and IgG levels in serum. There was a small increase in 
      IL-5 steady-state mRNA production in TRFK-5-treated mice after 2 h or 2 wk, but 
      this was not observed at other times examined. In untreated mice, IL-5 
      steady-state mRNA production in response to antigen challenge decreased > 6-fold 
      with age, although at all time points there was an increase in mRNA levels 
      following challenge. Therefore, at later times, 25 ng/ml rather than 230 ng/ml of 
      TRFK-5 inhibited BALF eosinophilia, probably because of reduced IL-5 levels. 
      Twenty-four weeks after treatment with TRFK-5, when challenge-induced 
      eosinophilia was restored, there was an excess of CD4(+) T cells in BALF from 
      challenged mice. However, these T cells had no measurable effects on other 
      responses to challenge, including cytokine production, B-cell accumulation, and 
      immunoglobulin production in serum. Thus, the biologic duration of TRFK-5 was 
      several months, and its activity was due to the presence of antibody above a 
      therapeutic threshold rather than to any profound effect on the immune system.
FAU - Garlisi, C G
AU  - Garlisi CG
AD  - Allergy and Immunology, Schering-Plough Research Institute, Kenilworth, New 
      Jersey 07033-0539, USA. charles.garlisi@spcorp.com
FAU - Kung, T T
AU  - Kung TT
FAU - Wang, P
AU  - Wang P
FAU - Minnicozzi, M
AU  - Minnicozzi M
FAU - Umland, S P
AU  - Umland SP
FAU - Chapman, R W
AU  - Chapman RW
FAU - Stelts, D
AU  - Stelts D
FAU - Crawley, Y
AU  - Crawley Y
FAU - Falcone, A
AU  - Falcone A
FAU - Myers, J G
AU  - Myers JG
FAU - Jones, H
AU  - Jones H
FAU - Billah, M M
AU  - Billah MM
FAU - Kreutner, W
AU  - Kreutner W
FAU - Egan, R W
AU  - Egan RW
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Am J Respir Cell Mol Biol
JT  - American journal of respiratory cell and molecular biology
JID - 8917225
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Interleukin-5)
RN  - 0 (RNA, Messenger)
RN  - 207137-56-2 (Interleukin-4)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/blood/*therapeutic use
MH  - B-Lymphocytes/immunology
MH  - Bronchoalveolar Lavage Fluid/cytology
MH  - Disease Models, Animal
MH  - Eosinophilia/complications/therapy
MH  - Interleukin-4/biosynthesis
MH  - Interleukin-5/biosynthesis/genetics/*immunology
MH  - Male
MH  - Mice
MH  - Pneumonia/blood/complications/*therapy
MH  - RNA, Messenger/blood
MH  - T-Lymphocytes/immunology
EDAT- 1999/01/28 00:00
MHDA- 1999/01/28 00:01
CRDT- 1999/01/28 00:00
PHST- 1999/01/28 00:00 [pubmed]
PHST- 1999/01/28 00:01 [medline]
PHST- 1999/01/28 00:00 [entrez]
AID - 10.1165/ajrcmb.20.2.3327 [doi]
PST - ppublish
SO  - Am J Respir Cell Mol Biol. 1999 Feb;20(2):248-55. doi: 10.1165/ajrcmb.20.2.3327.