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Methods of use for IL-22 in the treatment of gastrointestinal graft vs. host disease

A technique of graft-versus-host and gastrointestinal tract, which is applied to the preparation method of peptides, chemical instruments and methods, medical preparations containing active ingredients, etc.

Inactive Publication Date: 2016-10-12
纪念斯隆–凯特林癌病中心 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Current strategies to reduce clinical GVHD have the adverse effect of limiting post-transplant immune function and (favorable) graft-versus-leukemia / lymphoma (GVL) response to therapy

Method used

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  • Methods of use for IL-22 in the treatment of gastrointestinal graft vs. host disease
  • Methods of use for IL-22 in the treatment of gastrointestinal graft vs. host disease
  • Methods of use for IL-22 in the treatment of gastrointestinal graft vs. host disease

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Experimental program
Comparison scheme
Effect test

Embodiment I

[0181] This example describes the materials and methods used herein.

[0182] Materials and methods:

[0183] C57BL / 6 (CD45.2B6, H-2b), B6.SJL-Ptprca Pepcb / BoyJ (CD45.1B6 con-genic, H-2b), Il 12b- / -B6, BALB / c (H-2d) and LP (H-2b) Mice were obtained from Jackson Laboratories. B6 and BALB / cl22- / - mice were provided by Genentech, which is the anti-IL-22 neutralizing antibody 8E11. Lgr5-LacZ and Lgr5-GFP B6 mice were provided by H. Clevers (Barker et al., 2007). The BMT procedure was performed as previously described (Petrovic et al., 2004), BALB / c hosts received fractionated lethal radiation of 850 cGy to the bone marrow (5x 106 ), depleted of anti-Thy-1.2 and low-TOX-Mrabbit complement (Cedarlane assay chamber), or B6 hosts that received T cell-depleted bone marrow (5×10 6 ) by lethal irradiation with 1100 cGy fractions. Donor T cells (typically 1×106B6 or 4x106LP, unless otherwise stated), by collecting donor splenocytes and purifying them through nylon wool channels (usual...

Embodiment II

[0220] Host-derived IL-22 is important for limiting mortality and post-transplantation GVHD pathology.

[0221] Depletion of recipient IL-22 increases post-transplantation mortality: Given the reported protective role of IL-22 in GI tissue injury, we set out to assess the function of IL-22 after BMT.

[0222] IL-22 knockout (KO) receptors demonstrated a slight ( figure 1 A) and more ( figure 1 B) Increased mortality after antigen-mismatched BMT, as in wild-type (WT) recipients systemically treated with an anti-IL-22 neutralizing antibody ( figure 1 C). IL-22 in the donor bone marrow ( figure 1 D) or T cells ( figure 1 Deficiency in E) had no observable effect on the results. The reduced BMT intensity (low T cell and radiation dose) in hematopoietic chimeras suggests that IL-22 deficiency limits increased GVHD mortality in the host hematopoietic compartment ( figure 1 F), Implantation of IL-22KO receptors resulted in increased histopathological evidence of GI GVHD ( fig...

Embodiment III

[0231] Daily IP administration of rIL-22

[0232] LP was clinically mimicked in a C57BL / 6(B6) mild antigen mismatch model with T cell-depleted bone marrow and implantation of MACS-purified T cells from lethally irradiated mice. From the seventh day after HCT, the recipients were administered daily with PBS or 4ug murine recombinant (r) IL-22 by intraperitoneal (IP) injection. This arrangement is based on the results of the pharmacokinetics of rIL-22 tested in non-transplanted mice.

[0233] Daily IP administration of rIL-22 after three weeks of HCT resulted in decreased GVHD pathological responses in recipient small intestine, large intestine and liver ( Figure 9 , P<0.001). No differences were observed in skin histopathology, consistent with our previous finding that IL-22-deficient receptors demonstrate equivalent skin GVHD. Further evaluation of intestinal pathological responses showed that the rIL-22 receptor reduced intestinal crypt cell apoptosis in both the small an...

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Abstract

The disclosure provides methods and compositions for the use of IL-22 for treating conditions of intestinal injury and inflammatory conditions such as graft vs. host disease. Specifically, IL-22 can be used to increase Intestinal Stern Cell (ISC) recovery and for enhancing immune reconstitution following allogeneic hematopoietic transplantation. More specifically, the disclosure provides methods of using therapeutic IL-22, including a dimeric form of IL-22, in therapeutic compositions for treating graft vs. host disease, including hepatic, thymic, gastrointestinal, or other graft vs. host disease in hematopoietic stem cell transplant patients and in patients with inflammatory intestinal conditions.

Description

[0001] Cross reference to related applications [0002] This application claims priority to US Provisional Application No. 61 / 901,151, filed November 7, 2013, which is incorporated herein in its entirety. [0003] Statement of Government Rights [0004] This invention was made with United States Government support under Grant Nos. K08KHL115355A and P01CA023766 awarded by the National Institutes of Health. The US Government has certain rights in this invention. technical field [0005] The present invention provides methods and compositions for using IL-22 to treat intestinal injury disorders and inflammatory disorders such as graft-versus-host disease. Specifically, IL-22 can be used to enhance intestinal stem cell (ISC) recovery and to enhance immune reconstitution after allogeneic hematopoietic transplantation. In a particularly preferred embodiment, the present invention provides for the use of therapeutic IL-22, including dimerized forms of IL-22, in therapeutic composi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K38/00C07K1/00C07K14/00
CPCC07K14/54A61K38/20A61P1/00A61P37/06A61P37/08A61K35/747A61K2300/00C07K16/42
Inventor 马塞尔·范登布林克艾伦·哈纳斯卡洛琳·林德曼斯汤姆·唐
Owner 纪念斯隆–凯特林癌病中心
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