Mononuclear phagocytes and their use to promote axonal...

Details Mononuclear phagocytes and their use to promote axonal... Mononuclear phagocytes and their use to promote axonal...

1998-03-11

2001-07-31

Allen, Marianne P. (Department: 1631)

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

Animal or plant cell

C424S093700, C424S520000, C424S570000

Reexamination Certificate

active

06267955

ABSTRACT:

1. FIELD OF THE INVENTION
The present invention relates to compositions comprising mononuclear phagocytes, and to methods for using mononuclear phagocytes, to promote axonal regeneration in mammals affected by injury or disease of the central nervous system, as well as to compositions and methods for enhancing the therapeutic capacity of mononuclear phagocytes to promote axonal regeneration. In particular, the invention relates to (a) pharmaceutical compositions comprising, and methods for administering, stimulated or non-stimulated allogeneic mononuclear phagocytes at or near a site of the mammalian central nervous system affected by injury or disease to promote axonal regeneration, (b) compositions and methods for stimulating mononuclear phagocytes so as to enhance their capacity to promote axonal regeneration, and (c) methods for screening tissues, cells, proteins, peptides and other biologically active agents for their ability to stimulate mononuclear phagocytes for promoting axonal regeneration.
2. BACKGROUND OF THE INVENTION
Following axonal injury, neurons of the mammalian central nervous system (CNS) have a poor capacity for axonal regeneration. By contrast, neurons of the mammalian peripheral nervous system (PNS) have a substantially greater capacity for axonal regeneration. See Schwartz et al., 1989, FASEB J. 3:2371-2378.
The difference between axonal regeneration in the CNS and PNS has been attributed to the cellular environment of the neurons rather than to the neurons themselves. Following neuronal injury, the Schwann cells that surround PNS neurons are modulated so as to become permissive or supportive for axonal regeneration. By contrast, the astrocytes, oligodendrocytes and microglia that surround CNS neurons do not show such modulation and remain unsupportive or inhibitory for axonal regeneration. See Schwartz et al., 1987, CRC Crit. Rev. Biochem. 22:89-110.
This lack of modulation has been correlated with differences in the post-injury inflammatory response. See Perry and Brown, 1992, Bioessays 14:401-406; Lotan and Schwartz, 1994, FASEB J. 8:1026-1033. In particular, the accumulation of mononuclear phagocytes in response to CNS injury is delayed and limited in comparison with the response to injury in the PNS. This limited CNS mononuclear phagocyte response may in turn lead to (1) inefficient removal of the myelin debris that reportedly inhibits axonal regeneration, and (2) suboptimal release of macrophage-derived cytokines that would promote modulation of astrocytes and oligodendrocytes so as to support axonal regeneration.
The above observations have prompted speculation that appropriate modulation of the macrophage response might promote axonal regeneration after CNS injury. In an in vitro system, David et al. showed that when cryostat sections of normal rat optic nerve are co-cultured with mononuclear phagocytes derived from lesions of the rat CNS, the optic nerve sections show enhanced adhesiveness for embryonic chick dorsal root ganglion cells. David et al., 1990, Neuron 5:463-469. Conditioned medium from activated peritoneal macrophages was also effective in promoting adhesiveness of optic nerve sections in this in vitro assay.
However, results derived from in vivo models of CNS injury have revealed that some interventions that enhance the macrophage response to CNS injury do not result in enhanced regeneration. For instance, local injection of either tumor necrosis factor alpha (TNF-&agr;) or colony stimulating factor-1 (CSF-1) enhanced the macrophage response to experimental optic nerve injury. However, only TNF-&agr;, but not CSF-1, increased the permissiveness of the injured optic nerves for neuronal adhesion as assayed in vitro. Lotan et al., 1984, Exp. Neurol. 126:284-290. It has been suggested as one possible explanation that “only appropriately stimulated macrophages can influence neuronal regeneration.” Schwartz et al., 1994, Progress Brain Res. 103:331-341, at 338.
In fact, contrary to the teaching of the present invention, other investigators have reported that mononuclear phagocytes might exacerbate damage or limit recovery following CNS injury. Brain macrophages, when stimulated by cytokines, exhibit neurotoxic activity. Chamak et al., 1994, J. Neurosci. Res. 38:221-233. Pharmacological inhibition of mononuclear phagocyte function has been reported to promote recovery in a rabbit model of spinal cord injury. Giulian and Robertson, 1990, Annals Neurol. 27:33-42. It has been suggested that macrophage-derived cytokines may promote formation of glial scars and thereby inhibit axonal regeneration. Khan and Wigley, 1994, NeuroReport 5:1381-1385; Vick et al., 1992, J. Neurotrauma 9:S93-S103.
Citation or identification of any reference in Section 2 (or any other section) of this application shall not be construed as an admission that such reference is available as prior art to the present invention.
3. SUMMARY OF THE INVENTION
The present invention is directed to methods, and compositions, for use of allogeneic mononuclear phagocytes to promote axonal regeneration in the central nervous system of a mammal. The allogeneic mononuclear phagocytes are administered into the CNS at or near a site of injury or disease.
Allogeneic mononuclear phagocytes useful for the methods and compositions of the invention include, but are not limited to, allogeneic monocytes, macrophages and dendritic cells, and autologous monocytes, macrophages and dendritic cells.
The present invention further provides methods, and compositions, for stimulating allogeneic mononuclear phagocytes so as to enhance their capacity to promote axonal regeneration, and methods and compositions for use of stimulated allogeneic mononuclear phagocytes to promote axonal regeneration in the central nervous system of a mammal. The mononuclear phagocytes are stimulated by culturing them together with suitable tissue or suitable cells, or by culturing the mononuclear phagocytes in medium that has been conditioned by suitable tissue or suitable cells. Tissues suitable for this purpose include, without limitation, nerve segments (especially segments of peripheral nerve), dermis, synovial tissue, tendon sheath, liver, and other regenerating tissues. Skin obtained by punch biopsy is especially preferred for this purpose. Alternatively, the mononuclear phagocytes are stimulated by culturing them in medium to which at least one suitable biologically active agent has been added. Biologically active agents suitable for this purpose include, without limitation, neuropeptides; cytokines, for instance transforming growth factor-&bgr; (TGF-&bgr;), &bgr;-interferon (IFN-&bgr;), &ggr;-interferon (IFN-&ggr;), tumor necrosis factor &agr; (TNF-&agr;), interleukin 2 (IL-2), interleukin 3 (IL-3), interleukin 4 (IL-4), interleukin 10 (IL-10) and monocyte chemotactic and activating factor (MCAF); colony stimulating factors, for instance macrophage colony stimulating factor (M-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF) and colony stimulating factor 1 (CSF-1); neurotrophic factors, for instance neurotrophic factor 3 (NT-3), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF); and other biologically active molecules, for instance lipid A, the tripeptide fMet-Leu-Phe (fMLP), muramyl dipeptide (MDP), the ionophore A23187, and vitamin D3 binding protein. A biologically active protein or peptide may be used in its native or recombinant form.
CNS administration of mononuclear phagocytes may optionally be combined with administration of an adjuvant factor (e.g. aFGF) to the CNS, anti-inflammatory therapy of the mammal, or both.
The present invention further provides an assay for screening or identifying additional tissues, cells and biologically active agents that are suitable for stimulating mononuclear phagocytes to enhance their capacity to promote axonal regeneration. According to this assay, mononuclear phagocytes are first cultured together with the tissue or cells to be tested, or in medium that has been conditioned by the tissue or cells to be tested or in medium to which has be

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