Recombinant production of chemotactic CP-10 polypeptides and the

Details Recombinant production of chemotactic CP-10 polypeptides and the Recombinant production of chemotactic CP-10 polypeptides and the

1993-04-23

1998-03-24

Fitzgerald, David L.

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

536 235, 536 2431, 530350, 530351, 530413, 4353201, 435325, 4352523, 43525411, 514 2, C07K 1452, C12N 1519

Patent

active

057311668

DESCRIPTION:

BRIEF SUMMARY
This invention relates to a novel chemotactic factor, to the purification and characterisation of this factor from natural sources, and to the preparation of this factor as a synthetic or recombinant product. The invention further extends to analogues of the novel chemotactic factor, as well as to mutants, fragments and derivatives thereof. The invention also extends to antibodies to this factor (both polyclonal and monoclonal), to pharmaceutical compositions comprising the factor or the antibodies thereto, and to the therapeutic or diagnostic use of the factor or the antibodies thereto.
Leukocyte recruitment is vital for most inflammatory and immunologically-mediated responses. Chemotactic factors (CFs) released locally mediate directed migration of leukocytes and thus play an important role in the accumulation of these cells. Numerous CFs have been described including activated complement components (C5a, C3b), products of the activated coagulation cascade (kinins, thrombin, fibrino-peptides), bacterial and viral products, products of platelets, fibroblasts and neutrophils as well as the low molecular weight mediators leukotriene B4 and platelet activating factor (PAF) (reviews 1,2).
The delayed-type hypersensitivity (DTH) reaction is a widely studied example of cellular immunity. It is charcterised by accumulation, over 4-48 hr. of leukocytes at the site of intradermally-injected antigen in a sensitised subject. Polymorphonuclear leukocytes (PMNs) and monocytes are dominant in the lesion. The development of the reaction is considered to be due to the integrated release of numerous cytokines which not only control blood flow and vascular permeability but also determine the composition of the inflammatory infiltrate. It has been suggested that there may be a selective advantage in having a variety of factors (as evidenced by the number of CFs with activity towards, for example, PMNs) released under specific conditions and acting in particular micro-environments (3). Furthermore, the leukocyte composition of the inflammatory infiltrate depends on the temporal stage of the lesion and the nature of the stimulus. Thus activated lymphocytes may produce factors which are distinct from those derived from monocytes. Ward et. al. (4) and Altman (5) originally described the induction of CF when antigen was added to sensitised lymphocytes and the activity was attributed to a 12.5 kD protein (called lymphocyte-derived CF:LDCF). LDCF appears at the site of antigen challenge prior to macrophage influx (6) and has been extracted from DTH lesions (7). Miura et. al. (8) showed that activated Lyt 1+2-T lymphocytes from murine spleen were primarily responsible for the production of a macrophage CF but this factor has not been characterised and its relationship to the recently-described interleukin 8 family of monocyte-derived CFs (reviews 3,9) is unknown.
It has been previously proposed that fibrin, formed as a consequence of activated cell-mediated immunity (CMI), may enmesh infiltrating macrophages and maintain them at the inflammatory site (10). The generation of procoagulant by human monocytes reacting with microbial antigens is a close in vitro correlate of DTH reactions in man (11) and parallels the capacity of different mouse strains to develop DTH (12). Studies suggest that fibrin deposition at extravascular sites is mediated by macrophage procoagulant activity induced by an apparently unique T-cell derived product, macrophage procoagulant inducing factor (MPIF; 13-15).
Preliminary studies describing the characterisation of murine MPIF indicated activity associated with two heparin-binding peptides (.alpha. and .beta.) with pls of 8.5 and 9.0 respectively (14). On the basis of studies with other recombinant cytokines, depletion of activity with antibodies (Ab) to some cytokines and a variety of bioassays, MPIF was proposed to be a newly described factor. Furthermore, chromatographic fractions highly enriched for MPIF induced strong responses characterised by an intense infiltrate of PMNs after 4 hrs and of both PMNs

REFERENCES:
Chemical Abstracts, vol. 109, No. 19, Nov. 1988, Ryan, Janes et al: "Macrophage procoagulant-inducing factor. In vivo properties and chemotactic activity for phagocytic cells". pp 570.
Chemical Abstracts, Nol 111, Nol 21, Nov. 1989: Yoshizuka, Naonobu et al: "Macrophage chemotactic factor (MCF) produced by a human T cell hybridoma clone". pp. 598.
Bildau, H., et al (1989) Exp. Cell Biology, 57 (2): p. 123, abst. No. 94.
Lackmann, M., et al., J. Biol. Chem. 267: 7499-7904, 1992.
Lackmann, M, et al., J. Immunol. 150: 2981-91, 1993.
Lagasse et al., Mol. Cell. Biol. 8: 2402-10, 1988.
Lagasse, E., et al., Blood 79: 1907-15, 1992.
Odink, K., et al., Nature 330: 80-82, 1987.
Ryan, J., et al., J. Immunol. 141: 2110-17, 1988.
Ryan, J., et al., Immunol. Cell Biol. 65: 127-39, 1987. pages provided!.

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