Combined therapy of alpha-1-antitrypsin and temporal t-cell depletion for preventing graft rejection

a technology of temporal t cell depletion and graft rejection, which is applied in the direction of antibody medical ingredients, immunological disorders, peptide/protein ingredients, etc., can solve the problems of delayed onset acute rejection or acute rejection of grafts, and achieve the effect of prolonging the survival of xenografts

Inactive Publication Date: 2015-01-08
BEN GURION UNIVERSITY OF THE NEGEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]It is now disclosed, for the first time, that islet xenotransplant survival is remarkably extended by a combination therapy of AAT treatment and temporary T cell depletion. As exemplified herein below, xenograft recipients were treated separately with AAT or T cell depletion, however, this resulted in acute rejection, or delayed-onset acute rejection of the graft, respectively. Further, combination therapy of AAT with co-stimulation blockade using anti-CD154 / LFA-1 antibodies did not result in significant change in xenotransplant rejection. Surprisingly, co-administration of AAT and T cell depletion using anti-CD4 and anti-CD8 antibodies resulted in prolonging xenograft survival.

Problems solved by technology

As exemplified herein below, xenograft recipients were treated separately with AAT or T cell depletion, however, this resulted in acute rejection, or delayed-onset acute rejection of the graft, respectively.

Method used

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  • Combined therapy of alpha-1-antitrypsin and temporal t-cell depletion for preventing graft rejection
  • Combined therapy of alpha-1-antitrypsin and temporal t-cell depletion for preventing graft rejection
  • Combined therapy of alpha-1-antitrypsin and temporal t-cell depletion for preventing graft rejection

Examples

Experimental program
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Effect test

example 1

hAAT Monotherapy During Rat-to-Mouse Islet Transplantation

[0086]The initial dose for hAAT monotherapy (60 mg / kg from 1 day prior to transplantation) was selected from previous reports. In order to explore a higher impact monotherapy protocol, both a higher dose was examined (240 mg / kg) and an extended 10-day pretreatment protocol was tested. hAAT injections were repeated every 3 days in all experiments. A total of n (number in group)=6 mice were grafted under these conditions, including two recipients per modified protocol. In addition, n=6 mice were grafted with no added therapy, as control. As shown in FIG. 1A, neither of the three modified hAAT monotherapy protocols delayed islet xenograft rejection day (CT 10,11,12,13,15, 22 and hAAT 11, 12, 13, 14, 15, 24). The extended hAAT protocol is thereby used throughout the following studies.

[0087]Intragraft changes were examined (FIG. 1B-D). According to histology on day 7 post-transplantation (n=3 per group, representative images), inf...

example 2

DLN Molecular Profile During hAAT Monotherapy

[0089]In order to achieve a robust immune response, improve detection of changes in DLN, and achieve responses with low variability, skin xenotransplantation was performed. Treatment groups included control mice and mice receiving hAAT. Day-14 inguinal DLN were collected for FACS analysis. As shown in FIG. 2A, the number of B cells in the lymph nodes rose by 22.4% on average in transplanted mice, compared to control non-grafted mice. However, hAAT-treated mice displayed a 54.2% decrease on average of B cells from skin transplanted untreated mice. Surface levels of CD40 significantly increased compared to non-grafted mice, and then reduced with hAAT treatment (FIG. 2A).

[0090]DLN RT-PCR analysis was performed 3 days after transplantation. FIG. 2B depicts relative changes in specific transcript numbers. While DLN CD40, IL-6 and IL-10 transcript levels did not increase after xenotransplantation at this time point, CD86 displayed a significant...

example 3

Islet Xenotransplant Survival is Extended under hAAT and Temporary T Cell Depletion Combination

[0091]Since monotherapy with hAAT appears to have allowed an uninterrupted xeno-response, we sought to examine the combination of hAAT treatment with a technique for modifying xenoimmunity, namely, temporary T cell depletion.

[0092]Debulking therapy was examined alone and in combination with hAAT (FIG. 3A-E and FIG. 4). Recipient mice were treated with single-dose anti-CD8 / CD4 depleting antibodies, with or without hAAT (n=5-7 per group). According to circulating mouse CD45+CD3+ follow-up (FIG. 3A, representative result), mice injected with depleting antibodies exhibited a decrease in the relative number of circulating T cells and a spontaneous return to normal lymphocyte levels after a period of approximately two weeks.

[0093]As shown in FIG. 3B, animals treated by debulking therapy (DB) displayed a delay in xenograft rejection (days 28, 31, 31, 33, 33, 40, 52). In contrast, combined debulki...

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Abstract

The present invention provides compositions and methods for the prevention and treatment of aggressive immune processes to life-saving grafts, such as xenograft rejection, and for attenuating host responses in transplantation of tissues, cells and organs. More specifically, the compositions and methods of the present invention relate to combined therapies comprising treatment of alpha-1-antitrypsin (AAT) and temporary T-cell depletion including but not limited to anti-CD4 and anti-CD8 antibodies.

Description

FIELD OF THE INVENTION[0001]The present invention relates to compositions and methods for the prevention and treatment of graft rejection, including xenograft rejection, and for attenuating host responses in transplantation of cells, pancreatic islets, tissues and organs. More specifically, the compositions and methods of the present invention relate to combined therapies comprising treatment of alpha-1-antitryp sin and temporary T-cell depletion in the graft recipient.BACKGROUND OF THE INVENTION[0002]Transplantation systems such as organ transplantations have become important, effective and at times the sole therapies for many life-threatening end-stage diseases. However, injurious immune responses are still the major barrier for successful transplantation. This is manifested in irreversible and life-threatening graft failure (host-versus-graft response, or HVG) or pathological immune reactivity of bone-marrow transplants graft-versus-host disease (GVHD). Importantly, current immun...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K38/57
CPCA61K38/57A61K39/3955A61K39/39541A61K38/14A61K38/191A61K38/217A61P37/06A61K2300/00A61K35/39A61K39/395A61K2039/505C07K16/40
Inventor LEWIS, ELI
Owner BEN GURION UNIVERSITY OF THE NEGEV
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