Inhibition of graft versus host disease

Details Inhibition of graft versus host disease Inhibition of graft versus host disease

1999-07-30

2001-07-10

Nolan, Patrick J. (Department: 1644)

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

Animal or plant cell

C424S278100, C424S613000, C424S810000, C422S024000

Reexamination Certificate

active

06258357

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to cellular compositions useful in medical treatments, processes for their preparation and their uses in medical treatments. More specifically, it relates to cellular compositions useful in alleviation of complications following allogeneic bone marrow transplantation, namely graft versus host disease in mammalian patients, especially in human patients, and to processes for preparation of such compositions of matter.
BACKGROUND OF THE INVENTION
Bone marrow transplantation, BMT, is indicated following a process which destroys bone marrow. For example, following intensive systemic radiation or chemotherapy, bone marrow is the first target to fail. Metastatic cancers are commonly treated with very intensive chemotherapy, which is intended to destroy the cancer, but also effectively destroys the bone marrow. This induces a need for BMT. Leukemia is a bone marrow malignancy, which is often treated with BMT after chemotherapy and/or radiation has been utilized to eradicate malignant cells. BMT is currently used for treatment of leukemias which are life-threatening. Some autoimmune diseases may be severe enough to require obliteration of their native immune systems which includes concomitant bone marrow obliteration and requires subsequent bone marrow transplantation. Alleviation of any but the most acute life-threatening conditions involving bone marrow disorders with BMT is, however, generally regarded as too risky, because of the likelihood of the onset of graft versus host disease.
Graft-versus-host disease, GVHD, is an immunological disorder that is the major factor that limits the success and availability of allogeneic bone marrow or stem cell transplantation (collective referred to herein as allo-BMT) for treating some forms of otherwise incurable hematological malignancies, such as leukemia. GVHD is a systemic inflammatory reaction which causes chronic illness and may lead to death of the host mammal. At present, allogeneic transplants invariably run a severe risk of associated GVHD, even where the donor has a high degree of histocompatibility with the host.
GVHD is caused by donor T-cells reacting against systemically distributed incompatible host antigens, causing powerful inflammation. In GVHD, mature donor T-cells that recognize differences between donor and host become systemically activated. Current methods to prevent and treat GVHD involve administration of drugs such as cyclosporin-A and corticosteroids. These have serious side effects, must be given for prolonged periods of time, and are expensive to administer and to monitor. Attempts have also been made to use T-cell depletion to prevent GVHD, but this requires sophisticated and expensive facilities and expertise. Too great a degree of T-cell depletion leads to serious problems of failure of engraftment of bone marrow stem cells, failure of hematopoietic reconstitution, infections, or relapse. More limited T-cell depletion leaves behind cells that are still competent to initiate GVHD. As a result, current methods of treating GVHD are only successful in limited donor and host combinations, so that many patients cannot be offered potentially life-saving treatment.
BRIEF REFERENCE TO THE PRIOR ART
International Patent Application No. PCT/CA97/00564 Bolton describes an autovaccine for alleviating the symptoms of an autoimmune disease in a mammalian patient, comprising an aliquot of modified blood obtained from the same patient and treated extracorporeally with ultraviolet radiation and an oxygen/ozone gas mixture bubbled therethrough, at an elevated temperature (42.5° C.), the autovaccine being re-administered to the same patient after having been so treated.
It is an object of the present invention to provide a process of alleviating the development of GVHD complications in a mammalian patient undergoing allo-BMT procedures.
SUMMARY OF THE INVENTION
According to the present invention, a patient being treated by allo-BMT is administered a composition containing T-cells obtained from an allogeneic donor, said T-cells having been subjected in vitro to oxidative stress to induce therein decreased inflammatory cytokine production coupled with reduced proliferative response. It appears that such oxidatively stressed allogeneic T-cells when injected into a mammalian patient, have a down-regulated immune response and a down-regulated destructive allogeneic response against the recipient, so that engraftment of the hematopoietic stem cells, administered along with or separately from the stressed T-cells, can take effect with significantly reduced risk of development of GVHD. The population of stressed T-cells nevertheless appears to be able to exert a sufficient protective effect on the mammalian system to guard against failure of engraftment and against infection, whilst the hematopoietic system is undergoing reconstitution, at least in part, by proliferation and differentiation of the allogeneic stem cells.
One aspect of the present invention provides, accordingly, a process of treating a mammalian patient for alleviation of a bone marrow mediated disease, with alleviation of consequently developed graft versus host disease (GVHD), which comprises administering to the patient allogeneic hematopoietic stem cells and allogeneic T-cells, at least a portion of said T-cells having been subjected to oxidative stress in vitro, prior to administration to the patient, so as to induce an altered cytokine production profile and a reduced proliferative response therein.
Another aspect of the present invention provides a population of mammalian T-cells, essentially free of stem cells, said T-cells having been subjected in vitro to oxidative stress so as to induce in said cells an altered cytokine production profile and a reduced proliferative response.
A further aspect of the present invention provides a process for preparing an allogeneic cell population for administration to a human patient suffering from a bone marrow mediated disease, which comprises subjecting, in vitro, a population of donor cells enriched in T-cells to oxidative stress to induce in said T-cells an altered cytokine production profile and a reduced proliferative response.


REFERENCES:
patent: 5980954 (1999-11-01), Bolton
patent: 96/37208 (1996-11-01), None
patent: 98/07436 (1998-02-01), None
Spaner et al. Abstract 4272, Blood Nov. 15, 1998.

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