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

a composition and immunosuppressive technology, applied in the field of compositions with immunosuppressive and lymphocyte homing activities, can solve the problems of toxic side effects, affecting the immune system, so as to reduce the therapeutic dose, prevent or treat the effect of resistance to transplantation, and improve immunosuppressive

Inactive Publication Date: 2005-04-28
WELFIDE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[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 marro

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

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

example 1

Effect of FTY720 on Rat Skin Allograft Survival in Major Histocompatibility Complex (MHC)-Incompatible System

[0075] A rat skin allograft survival assay employing MHC-incompatible rat strains as donor and acceptor has been described (Reference 21, specifically incorporated herein by reference). Two MHC-incompatible rat strains were selected, WKAH donor (RT1k) and F344 recipients (RT1IV1). Full-thickness skin grafts (2.0×2.0 cm square) were transplanted to the lateral thorax of recipients and wrapped with sterile, bactericidal gauze. The chest was then wrapped with an elastic bandage. Five days after transplantation, the wraps were removed and the grafts inspected daily for rejection. Rejection was defined as more than 90% necrosis of graft epithelium.

[0076] All skin grafts in control (vehicle-treated) groups were rejected in 6 to 7 days after the transplantation. FTY720 significantly prolonged graft survival at an oral dose of 0.1 mg / kg or more in a dose-dependent manner (FIG. 1). ...

example 2

Effects of FTY720 on Heterotopic Cardiac Allograft Survival in MHC-Incompatible Rat Strain System

[0079] The effect of FTY720 on heterotopic cardiac allograft survival was compared with those of CsA and TRL by using WKAH donor (RT1k) and ACI recipient (RT1av1) rats. This procedure is detailed in reference 23, specifically incorporated herein by reference. Hearts from donors were implanted in the cervical portion of recipients by the technique of Miller et al. (40). The pulmonary artery of the donor heart was anastomosed to the right external jugular vein of the recipient in an end-to-side manner. The donor's brachiocephalic artery was anastomosed to the left common carotid artery of the recipient in an end-to-end manner. The day of grafting was day 0 and cardiac arrest was defined as the last day of graft survival. A graft heart surviving over 100 days was considered an indefinite or long-term survivor.

[0080] The results are illustrated in FIG. 3. All cardiac allografts in control ...

example 3

Effect of FTY720 on Canine Renal Allograft Survival in Combination with CsA

[0082] In a canine renal allograft model, either azathioprine or mizoribine in combination with CsA was reported to show a significant prolongation of the graft survival as compared with each drug alone (27-28). The effect of FTY720 in combination with CsA on renal allograft survival was investigated by using mongrel donors and beagle recipients in dogs (24-26, specifically incorporated herein by reference). Kidneys from mongrel donor dogs were transplanted into beagle dogs in the right iliac fossa, and the recipient dogs were then nephrectomized bilaterally. Levels of serum creatine and blood urea nitrogen were measured to monitor survival. Graft rejection was defined as the day when either serum creatine levels increased to more than 10.0 mg / dL or blood urea nitrogen levels elevated to more than 200 mg / dL. As shown in FIG. 5, in control (vehicle-treated) group, levels of serum creatinine irreversibly eleva...

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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...

Claims

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Application Information

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IPC IPC(8): A61K31/13G01N33/49A61K31/135A61K45/00A61P37/06
CPCY10S514/885A61K31/135A61P37/06
Inventor CHIBA, KENJIADACHI, KUNITOMO
Owner WELFIDE CORP
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