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Immuno-modulatory composition

a technology of immunomodulatory composition and composition, applied in the field of immunomodulatory composition, can solve the problems of poorer candidates, patient death, organ failure, etc., and achieve the effect of reducing aggressive immune activity and considerable clinical benefi

Inactive Publication Date: 2015-12-24
YALE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes a new way to treat diseases where the immune system plays a role, like autoimmune disease and graft rejection. The approach uses small particles made of biodegradable material that target specific cells in the immune system, reducing their activity and promoting a more tolerant response. The particles also contain a protein called leukemia inhibitory factor (LIF), which can further help to reduce aggressive immune responses. The method can be applied to both patients with these diseases and to organ graft recipients.

Problems solved by technology

Even then, recipients are subject to progressive chronic rejection within the blood vessels of the transplanted organ due to an insidious process that is not controlled by current immunosuppressive drugs: such chronic vascular rejection eventually blocks the blood flow within the transplanted organ causing organ failure.
Without a new organ transplant—unlikely given the shortage of organs—or dialysis in the case of kidney graft recipients, the patient will die.
Those patients who are unfortunately regarded as being poorer candidates for transplant will rarely ever become recipients of much needed donor tissue.
Not only does the targeted mode of delivery bring immune-modulators to the site where they are needed, for example within the organ transplant, but also it reduces the overall exposure of the patient to bio-active components that may carry toxic side-effects at irrelevant sites.

Method used

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Examples

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Effect test

example 1

[0037]Experimental models in mice have identified a critical regulatory system in T lymphocytes wherein Foxp3—the master gene for regulatory tolerance—is itself regulated by axotrophin / MARCH-7 (an E3-ligase) and LIF. Not only does axotrophin / MARCH-7 directly regulate LIF release by T lymphocytes, but also both axotrophin / MARCH-7 and LIF are required for normal Foxp3 gene activity.

[0038]In humans, Foxp3 and axotrophin / MARCH-7 are co-expressed in peripheral blood cells. In patients who have received a bone marrow transplant, and also in patients who have received a kidney transplant, expression of Foxp3 and axotrophin / MARCH-7 positively correlate with good graft function (Muthukumarana et al 2007). These findings infer that the relationship between immune tolerance, axotrophin / MARCH-7 and—by extrapolation—LIF is valid in clinical patients and supports the present invention which adopts a novel tolerogenic therapeutic approach of targeted delivery of LIF to the site of immune activity....

example 2

[0089]This Example shows the effect of exogenous LIF on T cells activated by CD3 / CD8 ligation.

[0090]Genetically normal mouse spleen cells cultured in serum-free growth medium were activated by anti-CD3 and anti-CD28 in the presence or absence of 10 ng / ml LIF. As shown in FIG. 3, at 48 h exogenous LIF was found to have increased expression of Nanog, p53, and LIF genes, and decreased SOCS-3 gene expression.

[0091]It is therefore predicted that in vivo therapy using targeted delivery of LIF will similarly increase the expression of Nanog, p53, and LIF genes in a target cell, and depress SOCS-3 expression.

example 3

[0092]This Example shows that cell-derived LIF protein is linked to allo-tolerance, whereas release of IL6 protein is linked to allo-rejection.

[0093]Spleen cells from in vivo primed allo-tolerant, or allo-rejected, mice stimulated by donor antigen (i.e. irradiated donor-type spleen cells) in RPMI growth medium containing 10% FCS revealed that release of cell-derived LIF protein is linked to allo-tolerance, whereas release of IL6 protein is linked to allo-rejection (see FIG. 4).

[0094]It is therefore predicted that targeted delivery of LIF to CD4+ T cells in vivo will result in increases in the regulatory tolerant (Treg) lineage, whereas targeted delivery of IL6 will oppose induction of tolerance.

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Abstract

A composition for modulating the immune response in a mammal comprising a pharmaceutically acceptable carrier solution and a plurality of biodegradable nanoparticles, wherein the nanoparticles comprise a targeting moiety that is able to bind selectively to the surface of a T lymphocyte cell and / or of a vascular endothelial cell and wherein the nanoparticles further comprise leukaemia inhibitory factor (LIF). Nanoparticle-mediated targeted delivery of LIF can be used a means to guide tolerogenesis in a patient and has immediate clinical application for recipients of organ grafts and also for patients suffering from autoimmune disease.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 12 / 739,357 filed May 19, 2010, now U.S. Pat. No. 9,101,548, which is a 371 of International Patent Application No. PCT / GB2008 / 003626 filed Oct. 24, 2008, which claims priority to Great Britain Patent Application No. 0721081.8 filed Oct. 26, 2007. These applications are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]The invention is in the field of compositions for modulating and controlling the immune response in an animal, such as a human. Also concerned are methods for controlling immune response in an animal or in tissues and cells derived from an animal and which are to be utilised in cell and tissue transplantation.BACKGROUND OF THE INVENTION[0003]Immune-mediated diseases arise when errors occur within the immune system. Normally the immune response carries the potential to destroy foreign antigens whilst at the same time protecting...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/48A61K38/19
CPCA61K47/48869A61K47/48561A61K38/19A61K9/127A61K9/5153A61K47/6913A61K47/6925A61K47/6849A61P37/00A61P37/02A61P37/06B82Y5/00
Inventor METCALFE, SUSAN MARIEFAHMY, TEREK M.
Owner YALE UNIV
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