Morphogen-induced modulation of inflammatory response

Abstract

The present invention is directed to methods and compositions for alleviating tissue destructive effects associated with the inflammatory response to tissue injury in a mammal. The methods and compositions include administering a therapeutically effective concentration of a morphogen or morphogen-stimulating agent sufficient to alleviate immune cell-mediated tissue destruction.

Description

CROSS REFERENCE RELATIONSHIP TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of (1) U.S. Ser. No. 753,059, filed Aug. 30, 1991, which is a continuation-in-part of U.S. Ser. No. 667,274, filed Mar. 11, 1991, (2) U.S. Ser. No. 752,764, filed Aug. 30, 1991, which is a continuation-in-part of U.S. Ser. No. 667,274 and [Atty. Docket No. CRP-068] filed on even date herewith.FIELD OF THE INVENTION [0002] The present invention relates generally to a method for modulating the inflammatory response induced in a mammal following tissue injury. More particularly, this invention relates to a method for alleviating immune-cell mediated tissue destruction associated with the inflammatory response. BACKGROUND OF THE INVENTION [0003] The body's inflammatory response to tissue injury can cause significant tissue destruction, leading to loss of tissue function. Damage to cells resulting from the effects of inflammatory response e.g., by, immune-cell mediated tissue destructio...

AI Technical Summary

Benefits of technology

[0019] The present invention provides a method for alleviating the tissue destructive effects associated with activation of the inflammatory response following tissue injury. The method comprises the step of providing to the affected tissue a therapeutically effective concentration of a morphogenic protein (“morphogen”, as defined herein) upon tissue injury or in anticipation of tissue injury, sufficient to substantially inhibit or reduce the tissue destructive effects of the inflammatory response.

[0025] In another aspect of the invention, the morphogen is provided to tissue at risk of damage due to immune cell-mediated tissue destruction. Examples of such tissues include tissue grafts and transplanted tissue or organs, as well as any tissue or organ about to undergo a surgical procedure or other clinical procedure likely to either inhibit blood flow to the tissue or otherwise induce an inflammatory response. Here the morphogen or morphogen-stimulating agent preferably is provided to the patient prior to induction of the injury, e.g., as a prophylactic, to provide a cyto-protective effect to the tissue at risk.

[0026] The morphogens described herein are envisioned to be useful in enhancing viability of any organ or living tissue to be transplanted. The morphogens may be used to particular advantage in lung, heart, kidney, liver and pancreas transplants, as well as in transplantation and / or grafting of skin, gastrointestinal mucosa, bone marrow and other living tissues.

Problems solved by technology

The body's inflammatory response to tissue injury can cause significant tissue destruction, leading to loss of tissue function.

The damaged tissue also often is replaced by fibrotic tissue, e.g., scar tissue, which further reduces tissue function.

The secondary damage, resulting from the inflammatory response, often is the source of significant tissue damage.

It is well known that damage occurs to cells in mammals which have been deprived of oxygen.

When ischemia limits the oxygen supply and ATP is depleted, the affected cells may become irreversibly injured.

The ensuing inflammatory responses to this initial injury provide additional insult to the affected tissue.

It is thought that reperfusion injury may result in dysfunction to the endothelium of the vasculature as well as injury to the surrounding tissue.

Similarly, tissues and organs for transplantation also are subject to the tissue destructive effects associated with the recipient host body's inflammatory response following transplantation.

It is currently believed that the initial destructive response is due in large part to reperfusion injury to the transplanted organ after it has been transplanted to the organ recipient.

To date, preservation of organs such as lungs, pancreas, heart and liver remains a significant stumbling block to the successful transplantation of these organs.

A significant problem with many immunosuppressants is their low therapeutic index, requiring the administration of high doses that can have significant toxic side effect.

This loss of function is due primarily to destruction of the major structural components of the joint, cartilage and bone, and subsequent loss of the proper joint anatomy.

As a consequence of chronic disease, joint destruction ensues and can lead to irreversible and permanent damage to the joint and loss of function.

Surgical synovectomy has many limitations, including the risk of the surgical procedure itself, and the fact that a surgeon often cannot remove all of the diseased membrane.

Patients with psoriasis have a much greater incidence of arthritis (psoraitic arthritis), and generalized exfoliation and even death can threaten afflicted individuals.

No single therapy is ideal, and it is rare for a patient not to be treated with several alternatives during the relapsing and remitting course of the disease.

Whereas systematic treatment can induce prompt resolution of psoriatic lesions, suppression often requires ever-increasing doses, sometimes with toxic side effect, and tapering of therapy may result in rebound phenomena with extensions of lesions, possibly to exfoliation.

Clinically, patients with fulminant IBD can be severely ill with massive diarrhea, blood loss, dehydration, weight loss and ever.

The prognosis of the disease is not good and frequently requires resection of the diseased tissue.

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