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

A graft-versus-host, gastrointestinal technology, applied in chemical instruments and methods, medical preparations containing active ingredients, drug combinations, etc.

Pending Publication Date: 2021-02-23
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 treatment of gastrointestinal graft vs. host disease
  • Methods of use for IL-22 in treatment of gastrointestinal graft vs. host disease
  • Methods of use for IL-22 in treatment of gastrointestinal graft vs. host disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment I

[0183] This example describes the materials and methods used herein.

[0184] Materials and methods:

[0185] C57BL / 6 (CD45.2 B6, H-2b), B6.SJL-Ptprca Pepcb / BoyJ (CD45.1 B6 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 x 106 ) were lethally irradiated with 1100 cGy fractions. Donor T cells (typically 1×106 B6 or 4x106 LP, unless otherwise stated), were purified by collecting donor splenocytes and passing through nylon wool ...

Embodiment II

[0222] Host-derived IL-22 is important for limiting mortality and post-transplantation GVHD pathology.

[0223] 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.

[0224] IL-22 knockout (KO) receptors demonstrated increased mortality following mild (Fig. 1A) and more (Fig. 1B) antigen-mismatched BMT, as did wild-type systemically treated with an anti-IL-22 neutralizing antibody ( WT) receptor (Fig. 1C). Deficiency of IL-22 in donor bone marrow (Fig. 1D) or T cells (Fig. 1E) had no observable effect on the results. 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 (Fig. 1F), and implantation of IL-22 KO receptors results in GI GVHD histopathology The evidence is increasing (Fig. 2A).

[0225] L-22 is expresse...

Embodiment III

[0233] Daily IP administration of rIL-22

[0234] 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. Beginning on day seven after HCT, recipients were administered daily intraperitoneal (IP) injections of PBS or 4ug murine recombinant (r)IL-22. This arrangement is based on the results of the pharmacokinetics of rIL-22 tested in non-transplanted mice.

[0235] Daily IP administration of rIL-22 three weeks after 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 rIL-22 receptors reduced intestinal crypt cell apoptosis in both small and large intestines...

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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. K08 KHL115355A and P01 CA023766 awarded by the National Institutes of Health. The U.S. 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 co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/20A61P37/06A61P1/00C07K14/54
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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