Compositions and methods of using compositions with accelerated lymphocyte homing immunosuppressive properties

Abstract

The methods and compositions of the invention and the compounds used in the invention involve a novel immunosuppression mechanism, accelerated lymphocyte homing immunosuppression (ALH-immunosuppression). For example, the compound FTY720 specifically directs lymphocytes to the peripheral lymph nodes, mesenteric lymph nodes, and Peyer's patches. By reversibly sequestering lymphocytes in these tissues, the compounds can inhibit an immune response in a mammal. Understanding these mechanisms provides a novel immunosuppression therapy that can synergistically interact with other immunosuppressive compounds. Screening methods for identifying similar ALH-immunosuppression compounds are also described. The invention allows better treatments and therapies wherever an immunosuppression regimen is desired.

Description

BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] This invention relates to the chemistry and biology of compounds with immunosuppressive and lymphocyte homing activities and, more specifically, this invention relates to methods and comprises compositions for accelerating lymphocyte homing in a mammal. [0003] 2. Description of Related Art [0004] In general, compounds used to suppress the immune response attack certain immune cells. By either removing these cells from the immune system or hampering their ability to respond to chemical messengers, the number of cells participating in any immune response decreases. With fewer cells responding, the immune system cannot mount the same response reaction. The result is immunosuppression. [0005] The use of these compounds follows directly from our understanding of the immune response and the function of immune cells. Numerous publications in the art describe the molecular and cellular aspects of the immune response. Genera...

AI Technical Summary

Benefits of technology

[0013] In one embodiment, the invention provides a method of suppressing the immune response by accelerating lymphocyte homing to any of the mesenteric or peripheral lymph tissues or Peyer's patches. This embodiment can be used to suppress the immune response in a mammal and comprises administering an ALH-immunosuppressive compound. The ALH-immunosuppressive compounds of this invention functionally act by directing lymphocytes to specific locations or lymphoid tissues. This lymphocyte homing activity can be reversible, so that suspending treatment restores normal lymphocyte populations. The compounds may also act to selectively decrease populations of certain lymphocytes in blood or lymph tissue, such as specifically decreasing populations of circulating lymphocytes or spleen lymphocytes.

[0035] In yet another aspect, the invention relates to ALH-immunosuppressive compositions and methods employing these compositions. These compositions comprise a 2-aminopropane-1,3-diol compound, or a homolog or analog thereof, and / or a benzene compound, or a homolog or analog thereof. These compositions can be combined with one or more other immunosuppressive compounds, such as cyclosporin, azathioprine, tacrolimus, mycophenolate mofetil, or analogs or derivatives of these compounds, or steroids, or any other immunosuppressive compound. Because the mechanism of action of the ALH-immunosuppressive activity does not result in similar side effects as in many widely used immunosuppressive compounds, these compositions provide novel synergistic actions, which may allow reduced therapeutic doses.

[0036] The ALH-immunosuppressive compositions of this aspect of the invention show superior immunosuppressive effects and are useful themselves, or in methods, for the prevention or treatment of various indications such as immunosuppression in organ, cell, or bone marrow transplantation, various autoimmune diseases or various allergy diseases. Namely, the compositions of the present invention have pharmacological activities such as immunosuppressive activity or antimicrobial activity and therefore are useful for the prevention or treatment of resistance to transplantation or transplantation rejection of organs or tissues (such as heart, kidney, liver, lung, bone marrow, cornea, pancreas, intestinum tenue, limb, muscle, nervus, fatty marrow, duodenum, skin or pancreatic islet cell etc., including xeno-transplantation), graft-versus-host diseases by bone marrow transplantation, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, nephrotic syndrome lupus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes mellitus, type II adult onset diabetes mellitus, uveitis, nephrotic syndrome, steroid-dependent and steroid-resistant nephrosis, palmoplantar pustulosis, allergic encephalomyelitis, glomerulonephritis, etc., and infectious diseases caused by pathogenic microorganisms.

Problems solved by technology

However, the similar side effects of CsA and TRL prohibits their use together.

Compounds from the second group of similarly-acting chemicals each interfere with nucleoside synthesis in the immune cells, arresting their metabolism and their immune activity.

These compounds can also result in toxic side effects.

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