A large number of scientific articles concerning Proneuron's
technology have been published by prestigious journals.
Following is a list of the important articles (you may click on
an item to access the abstract from the PubMed site):
Rapalino O, Lazarov-Spiegler O, Agranov E, Velan GJ, Yoles
E, Fraidakis M, Solomon A, Gepstein R, Katz A, Belkin M,
Hadani M, Schwartz M. Implantation of stimulated
homologous macrophages results in partial recovery of
paraplegic rats. Nat Med. 1998 Jul;4(7):814-21.
Moalem G, Leibowitz-Amit R, Yoles E, Mor F, Cohen IR,
Schwartz M. Autoimmune T cells protect neurons from
secondary degeneration after central nervous system axotomy.
Nat Med. 1999 Jan;5(1):49-55.
Hauben E, Nevo U, Yoles E, Moalem G, Agranov E, Mor F,
Akselrod S, Neeman M, Cohen IR, Schwartz M.
Autoimmune T cells as potential neuroprotective therapy for
spinal cord injury. Lancet. 2000 Jan 22;355(9200):286-7.
Schwartz M, Yoles E. Self-destructive and self-protective
processes in the damaged optic nerve: implications for
glaucoma. Invest Ophthalmol Vis Sci. 2000 Feb;41(2):349-51.
Schwartz M, Yoles E. Neuroprotection: a new treatment modality
for glaucoma? Curr Opin Ophthalmol. 2000 Apr;11(2):107-11.
Kipnis J, Yoles E, Porat Z, Cohen A, Mor F, Sela M, Cohen
IR, Schwartz M. T cell immunity to copolymer 1 confers
neuroprotection on the damaged optic nerve: possible therapy
for optic neuropathies. Proc Natl Acad Sci U S A. 2000 Jun
Hauben E, Butovsky O, Nevo U, Yoles E, Moalem G, Agranov E,
Mor F, Leibowitz-Amit R, Pevsner E, Akselrod S, Neeman M,
Cohen IR, Schwartz M. Passive or active immunization
with myelin basic protein promotes recovery from spinal cord
contusion. J Neurosci. 2000 Sep 1;20(17):6421-30.
Fisher J, Levkovitch-Verbin H, Schori H, Yoles E, Butovsky
O, Kaye JF, Ben-Nun A, Schwartz M. Vaccination for
neuroprotection in the mouse optic nerve: implications for
optic neuropathies. J Neurosci. 2001 Jan 1;21(1):136-42.
Schori H, Kipnis J, Yoles E, WoldeMussie E, Ruiz G, Wheeler
LA, Schwartz M. Vaccination for protection of retinal
ganglion cells against death from glutamate cytotoxicity and
ocular hypertension: implications for glaucoma. Proc Natl
Acad Sci U S A. 2001 Mar 13;98(6):3398-403.
Schwartz M, Kipnis J. Protective autoimmunity: regulation
and prospects for vaccination after brain and spinal cord
injuries. Trends Mol Med. 2001 Jun;7(6):252-8.
Yoles E, Hauben E, Palgi O, Agranov E, Gothilf A, Cohen A,
Kuchroo V, Cohen IR, Weiner H, Schwartz M. Protective autoimmunity is a
physiological response to CNS trauma. J Neurosci. 2001 Jun
Kipnis J, Yoles E, Schori H, Hauben E, Shaked I, Schwartz M.
Neuronal survival after CNS insult is determined by a
genetically encoded autoimmune response. J Neurosci. 2001
Hauben E, Agranov E, Gothilf A, Nevo U, Cohen A, Smirnov I,
Steinman L, Schwartz M.
Posttraumatic therapeutic vaccination with modified myelin
self-antigen prevents complete paralysis while avoiding
autoimmune disease. J Clin Invest. 2001 Aug;108(4):591-9.
Hauben E, Ibarra A, Mizrahi T, Barouch R, Agranov E,
Schwartz M. Vaccination with a Nogo-A-derived peptide after
incomplete spinal-cord injury promotes recovery via a
T-cell-mediated neuroprotective response: comparison with
other myelin antigens. Proc Natl Acad Sci U S A. 2001 Dec
Kipnis J, Schwartz M. Dual action of glatiramer acetate
(Cop-1) in the treatment of CNS autoimmune and
neurodegenerative disorders. Trends Mol Med. 2002
Bakalash S, Kipnis J, Yoles E, Schwartz M. Resistance of
retinal ganglion cells to an increase in intraocular
pressure is immune-dependent. Invest Ophthalmol Vis Sci.
Schori H, Lantner F, Shachar I, Schwartz M. Severe
immunodeficiency has opposite effects on neuronal survival
in glutamate-susceptible and -resistant mice: adverse effect
of B cells. J Immunol. 2002 Sep 15;169(6):2861-5.
Kipnis J, Mizrahi T, Yoles E, Ben-Nun A, Schwartz M, Ben-Nur
A. Myelin specific Th1 cells are necessary for
post-traumatic protective autoimmunity. J Neuroimmunol. 2002
Sep;130(1-2):78-85. Erratum in: J Neuroimmunol 2002
Schwartz M, Kipnis J. Autoimmunity on alert: naturally
occurring regulatory CD4(+)CD25(+) T cells as part of the
evolutionary compromise between a 'need' and a 'risk'.
Trends Immunol. 2002 Nov;23(11):530-4. Erratum in: Trends
Immunol. 2003 Jan;24(1):12.
Kipnis J, Mizrahi T, Hauben E, Shaked I, Shevach E, Schwartz
M. Neuroprotective autoimmunity: naturally occurring
CD4+CD25+ regulatory T cells suppress the ability to
withstand injury to the central nervous system. Proc Natl
Acad Sci U S A. 2002 Nov 26;99(24):15620-5. Epub 2002 Nov
Hauben E, Schwartz M. Therapeutic vaccination for spinal
cord injury: helping the body to cure itself. Trends
Pharmacol Sci. 2003 Jan;24(1):7-12. Review.
Schwartz M, Shaked I, Fisher J, Mizrahi T, Schori H.
Protective autoimmunity against the enemy within: fighting
glutamate toxicity. Trends Neurosci. 2003 Jun;26(6):297-302.
Bakalash S, Kessler A, Mizrahi T, Nussenblatt R, Schwartz M.
Antigenic specificity of immunoprotective therapeutic
vaccination for glaucoma. Invest Ophthalmol Vis Sci. 2003
Hauben E, Gothilf A, Cohen A, Butovsky O, Nevo U, Smirnov I,
Yoles E, Akselrod S, Schwartz M. Vaccination with dendritic
cells pulsed with peptides of myelin basic protein promotes
functional recovery from spinal cord injury. J Neurosci.
2003 Sep 24;23(25):8808-19.
Bomstein Y, Marder JB, Vitner K, Smirnov I, Lisaey G,
Butovsky O, Fulga V, Yoles E. Features of skin-coincubated
macrophages that promote recovery from spinal cord injury. J
Neuroimmunol. 2003 Sep;142(1-2):10-6.
Knoller N, Auerbach G, Fulga V, Zelig G, Attias J, Bakimer R,
Marder JB, Yoles E, Belkin M, Schwartz M, Hadani M.
Clinical experience using incubated autologous macrophages
as a treatment for complete spinal cord injury: phase I
study results. J Neurosurg Spine. 2005 Sep;3(3):173-81.
Following are abstracts of some of the articles. For
more information please contact us at
stimulated homologous macrophages results in partial
recovery of paraplegic rats
O. Rapalino, O.
Lazarov-Spiegler, E. Agranov, G.J. Velan, E. Yoles, M.
Fraidakis, A. Solomon, R. Gepstein, A. Katz, M. Belkin,
M. Hadani and M. Schwartz
Nature Medicine, 4:814-821
Postinjury recovery in most
tissues requires an effective dialog with macrophages;
however in the mammalian central nervous system this
dialog may be restricted (possibly due to its
immune-privileged status), which probably contributes to
its regeneration failure. We circumvented this by
implanting pre-exposed ex vivo to peripheral nerve
segments, into transected rat spinal cord. This
stimulated tissue repair and partial recovery of motor
function, manifested behaviorally by movement of hind
limbs, plantar placement of the paws and weight support,
and electrophysiologically by cortically-evoked
hind-limb muscle response. We substantiated these
findings immunohistochemically by demonstrating
continuity of labeled nerve fibers across the transected
site and by tracing descending fibers distally to it by
anterograde labeling. In recovered rats, retransection
of the cord above the primary transection site led to
loss of recovery, indicating the involvement of long
descending spinal tracts. Injection of macrophages into
the site of injury is relatively non-invasive and, as
the cells are autologous, it may be developed into a
inflammatory reaction in the CNS: a key impediment to
O. Lazarov-Spiegler, O.
Rapalino, G. Agranov and M. Schwartz
Molec. Med. Today, 4:337-342
Axons in the central
nervous system (CNS) of adult mammals do not regenerate
after injury. Mammalian CNS differs in this respect from
other mammalian tissues, including the peripheral
nervous system (PNS) and from the CNS of lower
vertebrates. In most parts of the body, including the
nervous system, injury triggers an inflammatory reaction
involving macrophages. This reaction is needed for
tissue healing; when it is delayed or insufficient,
healing is incomplete. The CNS, although needing an
efficient inflammatory reaction resembling that in the
periphery for tissue healing, appears to have lost the
ability to supply it. We suggest that restricted CNS
recruitment and activation of macrophages are linked to
regeneration failure and might reflect the immune
privilege that characterizes the mammalian CNS. As
macrophages play a critical role in tissue restoration,
and because their recruitment and activation are among
the most upstream of the events leading to tissue
healing, overcoming the deficiencies in these steps
might trigger a self-repair process leading to recovery
after CNS injury.
stimulated macrophages are beneficial for optic nerve
O. Lazarov-Spiegler, A.S. Solomon
and M. Schwartz
Glia, 24:329-337 (1998).
We have previously
demonstrated that the failure of the mammalian central
nervous system (CNS) to regenerate following axonal
injury is related to its immunosuppressive nature, which
restricts the ability of both recruited blood-borne
monocytes and CNS-resident microglia to support a
process of repair. In this study we show that transected
optic nerve transplanted with macrophages stimulated by
spontaneously regenerative nerve tissue, e.g., segments
of peripheral nerve (sciatic nerve), exhibit axonal
regrowth at least as far as the optic chiasma. Axonal
regrowth was confirmed by double retrograde labeling of
the injured optic axons, visualized in their cell
bodies. Transplanted macrophages exposed to segments of
CNS (optic) nerve were significantly less effective in
inducing regrowth. Immunocytochemical analysis showed
that the induced regrowth was correlated with a wide
distribution of macrophages within the
transplanted-transected nerves. Concomitantly, it was
correlated with enhancement of clearance of myelin,
known to be inhibitory for regrowth and poorly
eliminated after injury in the CNS. These results
emphasize that healing of the injured mammalian CNS,
like healing of any other injured tissue, requires the
partnership of the immune system, which is normally
restricted, but that the restriction can be circumvented
by transplantation of peripheral nerve-stimulated
Potential Repair of
Rat Spinal Cord Injuries Using Stimulated Homologous
Michal Schwartz, Ph.D.; Orly
Lazarov-Spiegler, M.Sc.; Otto Rapalino, M.D.; Ivgenia
Agranov, M.D.; Gad Velan, M.D.; Moshe Hadani, M.D.
Neurosurgery, 44:1041-1046, (1999).
The failure of the adult
mammalian central nervous system (CNS) to regenerate
after injury has long been viewed as a unique phenomenon
resulting from the specific nature of this system. The
finding that some CNS axons could be induced to regrow
if provided with a permissive environment suggested that
this failure is a result, at least in part, of the
nature of the post injury neuronal environment. It was
further shown that the involvement of inflammatory
cells, particularly macrophages, in postinjury processes
in the CNS is limited. We have suggested that, to
achieve recovery after injury, the adult mammalian CNS
may require the assistance of the same postinjury
factors as those involved in the recovery of
spontaneously regenerating systems but that its
accessibility to such assistance is restricted.
Accordingly, we proposed that it might be possible to
circumvent the restriction, allowing regeneration to
occur. We showed that the implantation of autologous
macrophages, which had been prestimulated by exposure to
a regenerative (sciatic) nerve, into completely
transected spinal cords of adult rats led to partial
motor recovery. This treatment intervenes in the
postinjury process by simulating in the axotomized CNS
the events that occur naturally in spontaneously
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Proneuron Biotechnologies is engaged in research
related to spinal cord injuries and paralysis cure.