Use of interleukin-10 to produce a population of suppressor...

Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Primate cell – per se

Reexamination Certificate

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Details

C435S325000, C435S366000, C435S372000

Reexamination Certificate

active

06277635

ABSTRACT:

FIELD OF THE INVENTION
The invention relates generally use of interleukin-10 (IL-10) in producing a population of cells which act to suppress various immunological functions, e.g., methods for treating and inhibiting tissue rejection or other immune functions by administering to an afflicted individual an effective amount of interleukin-10.
BACKGROUND OF THE INVENTION
Interleukin-10 is a cytokine which was originally characterized by its activities in suppressing production of Th1 cytokines. See, e.g., de Vries and de Waal Malefyt (eds. 1995)
Interleukin
-10 Landes Co., Austin, Tex.; etc.
Suppression of immunological function finds utility in many different contexts. See, e.g., Paul (ed. 1995)
Fundamental Immunology
3d ed., Raven Press, NY. In particular, allogeneic immunity is important in a transplantation context, due largely to its extraordinary strength. As organ and tissue transplants becomes more common in medical contexts, the ability to minimize problems from tissue rejection exhibit larger economic advantages. In addition, means to minimize autoimmune conditions, to block certain responses to particulate antigens, e.g., bacterial and parasitic, and to minimize reaction to certain soluble antigens, both protein and allergens, will be significant advances for therapeutic purposes.
The lack of fully effective therapeutics to minimize or eliminate tissue rejection, graft vs. host disease, or these other immunological responses leads to many problems. The present invention addresses and provides solutions to many of these problems.
SUMMARY OF THE INVENTION
The invention relates to the use of the cytokine interleukin-10 (IL-10) to suppress the rejection of transplanted tissues. The invention also includes pharmaceutical compositions comprising interleukin-10. Preferably, the interleukin-10 of the invention is selected from the group consisting of the mature polypeptides of the open reading frames defined by the following amino acid sequences:
Met His Ser Ser Ala Leu Leu Cys Cys Leu Val Leu Leu Thr Gly

Va1 Arg Ala Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys

Thr His Phe Pro Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg

Asp Ala Phe Ser Arg Val Lys Thr Phe Phe Gln Met Lys Asp Gln

Leu Asp Asn Leu Leu Leu Lys Glu Ser Leu Leu Glu Asp Phe Lys

Gly Tyr Leu Gly Cys Gln Ala Leu Ser Glu Met Ile Gln Phe Tyr

Leu Glu Glu Val Met Pro Gln Ala Glu Asn Gln Asp Pro Asp Ile

Lys Ala His Val Asn Ser Leu Gly Glu Asn Leu Lys Thr Leu Arg

Leu Arg Leu Arg Arg Cys His Arg Phe Leu Pro Cys Glu Asn Lys

Ser Lys Ala Val Glu Gln Val Lys Asn Ala Phe Asn Lys Leu Gln

Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe Asp Ile Phe Ile

Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile Arg Asn (see SEQ ID NO:1),

and
Met Glu Arg Arg Leu Val Val Thr Leu Gln Cys Leu Val Leu Leu

Tyr Leu Ala Pro Glu Cys Gly Gly Thr Asp Gln Cys Asp Asn Phe

Pro Gln Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg Val Lys

Thr Phe Phe Gln Thr Lys Asp Glu Val Asp Asn Leu Leu Leu Lys

Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala

Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln

Ala Glu Asn Gln Asp Pro Glu Ala Lys Asp His Val Asn Ser Leu

Gly Glu Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His

Arg Phe Leu Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Ile

Lys Asn Ala Phe Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala

Met Ser Glu Phe Asp Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met

Thr Ile Lys Ala Arg (see SEQ ID NO:2),
wherein the standard three letter abbreviation is used to indicate L-amino acids, starting from the N-terminus. These two forms of IL-10 are sometimes referred to as human IL-10 (or human cytokine synthesis inhibitory factor (“CSIF”) and viral IL-10 (or BCRF1), respectively, e.g., Moore, et al., Science 248:1230-1234 (1990); Vieira, et al., Proc. Natl. Acad. Sci. 88:1172-1176 (1991); Fiorentino, et al., J. Exp. Med. 170:2081-2095 (1989); and Hsu, et al., Science 250:830-832 (1990). A homolog has also been described in equine herpesvirus type 2 (Roe, et al., Virus Genes 7:111-116 (1993)) as well a numerous counterparts from various species. More preferably, the mature IL-10 used in the method of the invention is selected from the group consisting of
Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe

Pro Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe

Ser Arg Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn

Leu Leu Leu Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu

Gly Cys Gln Ala Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu

Val Met Pro Gln Ala Glu Asn Gln Asp Pro Asp Ile Lys Ala His

Val Asn Ser Leu Gly Glu Asn Leu Lys Thr Leu Arg Leu Arg Leu

Arg Arg Cys His Arg Phe Leu Pro Cys Glu Asn Lys Ser Lys Ala

Val Glu Gln Val Lys Asn Ala Phe Asn Lys Leu Gln Glu Lys Gly

Ile Tyr Lys Ala Met Ser Glu Phe Asp Ile Phe Ile Asn Tyr Ile

Glu Ala Tyr Met Thr Met Lys Ile Arg Asn (see SEQ ID NO:3)

and

Thr Asp Gln Cys Asp Asn Phe Pro Gln Met Leu Arg Asp Leu Arg

Asp Ala Phe Ser Arg Val Lys Thr Phe Phe Gln Thr Lys Asp Glu

Val Asp Asn Leu Leu Leu Lys Glu Ser Leu Leu Glu Asp Phe Lys

Gly Tyr Leu Gly Cys Gln Ala Leu Ser Glu Met Ile Gln Phe Tyr

Leu Glu Glu Val Met Pro Gln Ala Glu Asn Gln Asp Pro Glu Ala

Lys Asp His Val Asn Ser Leu Gly Glu Asn Leu Lys Thr Leu Arg

Leu Arg Leu Arg Arg Cys His Arg Phe Leu Pro Cys Glu Asn Lys

Ser Lys Ala Val Glu Gln Ile Lys Asn Ala Phe Asn Lys Leu Gln

Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe Asp Ile Phe Ile

Asn Tyr Ile Glu Ala Tyr Met Thr Ile Lys Ala Arg (see SEQ ID NO:4).
Thus, in particular embodiments, the present invention provides a method of reducing or inhibiting graft vs. host disease in a bone marrow transfer in a mammal, comprising administering to the mammal an effective amount of interleukin-10. It also provides a method of inhibiting, by an immune system, an antigen-specific response to subsequent presentation of said antigen, comprising administering to said immune system an effective amount of exogenous interleukin-10 and that antigen. In preferred embodiments, the immune response is mediated by a macrophage, APC, langerhans cell, or dendritic cell; the method further inhibits proliferative response of CD4
+
host-reactive T cell clones; or the inhibiting persists for at least about 21 days. In other preferred embodiments, the effective amount is sufficient to decrease responder T cell activation; or may further comprise reduced stimulatory capacity of peripheral blood mononuclear cells, dendritic cells, monocytes, and/or normal B cells.
In another embodiment, the invention provides a substantially pure antigen-specific anergic T cell characterized by production upon restimulation of low IL-2; low IL-4; low IL-5; intermediate IFN-&ggr;; low GM-CSF; and high IL-10; with the population made by administering to precursors of said T cell with a combination of exogenous IL-10 and antigen. In preferred embodiments, the precursors are CD4
+
T cells; the cells further produce high TNF-&agr;; the cells induce an anergic response to the antigen; the administered IL-10 is human IL-10; the IL-10 is administered for at least about 7 days; and/or the anergic condition persists for at least about 21 days. The antigen specificity may be to an antigen is selected from a protein antigen; a particulate antigen; an alloantigen; or an autoantigen.
Another embodiment is a substantially pure antigen-specific anergic T cell characterized by production upon restimulation of low IL-2; low IL-5; intermediate IFN-&ggr;; low GM-CSF; and high IL-10. Typically, the levels of production of the cytokines is, for IL-2 less than about 500 pg/ml; for IL-5 between about 300 and 3000 pg/ml; for IFN-&ggr; at least about 1000 pg/ml; for GM-CSF between about 300-3000 pg/ml; and for IL-10 at least about 3000 pg/ml. Preferably, the IL-10 level upon restimulation with anti-CD3 is at least about 5× that of a Th1 cell.
The invention also embraces a substantially pure T cell which exhibits an antigen-specific anergy to an antigen, including, e.g., where the antigen is an alloantigen or self antigen; which produces IL-10 upon restimul

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