Flt3 inhibitors for immune suppression

A technology of kinase inhibitors and uses, applied in the field of FLT3 inhibitors for immunosuppression, capable of solving problems such as immunosuppression

Inactive Publication Date: 2013-08-21
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recently, therapies targeting the T-cell arm of the immune response, most of which are involved, often lead to severe immunosuppression

Method used

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  • Flt3 inhibitors for immune suppression
  • Flt3 inhibitors for immune suppression
  • Flt3 inhibitors for immune suppression

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0191] Treatment of DCs with FLT3 inhibitors and induction of apoptosis

[0192] When DCs were exposed to FLT3 inhibitors, the survival and function of DCs were tested. In the presence of adenoviral transfectants-single colony-stimulating factor (GM-CSF) + / - FL, mature DCs were cultured in dose-response assays and Corresponding to CEP701, 5214 and AG1296, a decrease in viable and stimulated DCs was observed.

[0193] Bone marrow (BM) was flushed with PBS from mouse extremities, and red blood cells (RBCs) were lysed in hypotonic buffer. -CSF) (1000U / ml) or GM+FL (100ng / ml) at a concentration of 2x106cells / ml cultured in a culture dish, remove the non-adherent cells on the 2nd, 4th and 6th day and before adding fresh medium Wash the adherent cells, collect non-adherent mature DCs on the 8th day, and re-culture in the absence or presence of CEP-701 at a concentration of 5 or 50 molar. After 24 hours, the cells are stained for FACS analysis , combined with MHC class II expressio...

example 2

[0197] Inhibition of FLT3 reduces DC-basal proliferation of T cells. In these cases, DCs were generated from BALBc mice as described above, the cells were detached from untreated or treated with CEP701, and then cultured with C57BL / 6 splenocytes at the ratios indicated, After 3 days, join 3 H and measure proliferation as Figure 2a showed that CEP701 had a robust effect on reducing hyperplasia, Figure 2b In , BALB / c splenocytes replaced DCs cells to test the inhibition of CEP701 in the standard mixed lymphocyte reaction (MLR), and the figure also showed that the response was similarly inhibited in the presence of CEP701.

[0198] To determine whether T cell stimulation responses were suppressed by exposure to AG1296, two different T cell proliferation measurements were performed, Figure 2c Shown are results from co-incubating allogeneic mice in the presence (10 μM) or absence of inhibitors, mixed lymphocyte reactions in this standard, equal numbers of stimulator and respon...

example 3

[0200] Direct treatment of T cells without inhibiting T cell proliferation

[0201] Due to the influence of inhibitors on DCs cells rather than T cells themselves, it is not shown that Figure 2a and the resulting suppression of b, 1x10 6 The T cells were cultured on the culture dish covered with anti-CD3, then the T cells were stimulated with anti-CD28, after 2 days, adding 3 H and measured proliferation, as shown, had no effect on directly stimulated T cells.

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Abstract

The invention refers to an FLT3 inhibitors for immune suppression. New methods are provided for suppressing the immune system and for treating immune related disorders. Therapies of the invention include administration of an FLT3 inhibitor compound to a subject in need thereof, such as a subject suffering from organ rejection, bone marrow transplant rejection, acquired immune deficiency syndrome, arthritis, aplastic anemia, graft-versus-host disease, Graves' disease, established experimental allergic encephalitomyelitis, multiple sclerosis, lupus, or a neurological disorder. Methods are also provided for screening therapeutic agents for treating immune disorders, including the use of a mouse having an elevated level of FLT3 receptor activity.

Description

[0001] The present invention is a divisional application of the Chinese patent application with the application number 200580031410.1, the application date is July 14, 2005, and the invention title is "FLT3 inhibitor for immunosuppression". [0002] Related applications [0003] This application claims priority from US Provisional Application No. 60 / 589,511, the teachings of which are incorporated herein by reference. technical field [0004] The present invention relates to methods for inhibiting cellular immune response, preventing or treating immune-related diseases and screening therapeutic agents for preventing or treating immune-related diseases. Therapy of the present invention comprises administering an inhibitor of FMS-associated tyrosine kinase 3 (FLT3) in need thereof to a patient, e.g., suffering from post-transplant organ rejection, bone marrow transplant rejection, graft-versus-host disease (GVHD), or Lupus patients. Methods of screening therapeutic agents for ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61P37/06A61P19/08A61P19/02A61P7/06A61P3/10A61P37/00A61P7/04A61P29/00A61P25/00A61P21/04A61P17/06
CPCA61K31/553A61P1/04A61P17/00A61P17/06A61P19/02A61P19/08A61P21/04A61P25/00A61P25/28A61P29/00A61P35/00A61P37/00A61P37/02A61P37/06A61P43/00A61P7/04A61P7/06A61P3/10
Inventor D·斯莫尔K·A·沃特比D·帕多略
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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