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Thomas J. Schall et al. m ^ £7 PATENT 

Application No.: 09/919,224 ^ x <*/ 

^ a * 56 BEST AVAILABLE COPY a 

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PRELIMINARY AMENDMENT O J fTl 
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IN THE SPECIFICATION: 3d fTl 



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IMMUNOLOGIC ACTIVITIES 

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OF RHESUS CYTOMEGALOVIRUS ENCODED IL- 1 0 ° 



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Please replace paragraph 48 with the following rewritten pa ragraph: 

-^HAs used herein, "rhesus cytomegalovirus interleukin 10" or "rhesus CMV IL-10" 
is defined as a protein which has an amino acid sequence having substantial identity to a. known 
sequence of rhesus CMV IL-10 as described in Lockridge et al, Virology (2000) 268:272-280, 
which is incorporated herein by reference. For the purposes of this invention, some methods use 
glycosylated {e.g., produced in eukaryotic cells such as yeast or CHO cells) rhesus CMV IL-10 
and some methods use unglycosylated {e.g., chemically synthesized or produced in prokaryotic 
cells, such as E. coli) rhesus CMV IL-10. 4 

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ifiAs used herein, "human cytomegalovirus interleukin 10" or "human CMV IL- 
10" is defined as a protein which has an amino acid sequence having substantial identity to a 
known sequence of human CMV IL-10 as discussed in Kotenko et al, PNAS (2000) 97(4):1695- 
1700, which is incorporated herein by reference. For the purposes of this invention, some 
methods use glycosylated {e.g., produced in eukaryotic cells such as yeast or CHO cells) human 
CMV IL-10 and some methods use unglycosylated {e.g., chemically synthesized or produced in 
prokaryotic cells such as E. coli) human CMV IL-lOif- 



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-^-Rhesus and human CMV IL-10 can be used in a number of in vitro or ex vivo 
methods. In some methods, cellular responses to these agents are analyzed to provide 
information to optimize dosage regimes of these agents in vivo. In some methods, rhesus and 




Thomas J. Schall et al. DCQT A\/A|| ARI E POPV PATENT 

Application No.: 09/919,224 DEO I ttVMBLttDLE Wf I 

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human CMV IL-10 are used as positive controls to screen other drugs for effects on lymphocyte - 
proliferation. If the positive control inhibits proliferation of the lymphocytes, whereas a 
candidate drug does not in a parallel reaction, then it can be concluded that the test drug is 
ineffective. In other methods, rhesus and human CMV IL-10 are used as research reagents to 
inhibit proliferation of cells and thereby analyze underlying cellular processes associated with 
cellular physiology. In other methods, proliferating PBMCs are obtained from a patient with an 
immune disorder. The lymphocytes are treated with rhesus CMV IL-10 or human CMV IL-10 
ex vivo and then returned to the patients.^ 

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^-Immune disorders preventable or treatable by methods of the invention include^ 
but are not limited to, the following!— 



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-Defects in the functioning of the cell-mediated immune response have been 
implicated in various cell-mediated cytotoxicity immune diseases, such as grafl-versus-host 
disease. Cytotoxic T lymphocytes (CTLs) are generated by the activation of T cytotoxic (T c ) 
cells. CTLs have lytic capability and are critical in the recognition and elimination of altered 
self-cells (e.g., virus-infected cells and tumors). Cytotoxic T lymphocytes (CTLs) are generally 
CD8 + are therefore class I MHC restricted. Since virtually all nucleated mammalian cells 
express class I MHC molecules, CTLs can recognize and eliminate almost any altered 
mammalian cell. This ability of CTLs to recognize and eliminate almost any altered mammalian 
cell can result in cell-mediated cytotoxicity related immune diseases. Consequently, a decrease 
in cell surface expression of class I MHC molecules is expected to ameliorate or prevent cell- 
mediated cytotoxicity related diseases. Thus, decreasing cell surface expression of class I MHC 
molecules in a patient suffering from a cell-mediated cytotoxicity immune disease by 
administering an effective dosage of rhesus CMV IL-10 or human CMV IL-10 would be 
beneficial. 



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Thomas J. Schall et al. 
Application No.: 09/919,224 
Page 4 



PATENT 



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Please replace paragraphs 83 and 84 with t he following rewritten paragraphs: 
j^l. Graft-versus-Host Disease 
Graft-versus-host disease (GVHD) occurs as a result of in vivo cell-mediated 
cytotoxicity. The disease develops when immunocompetent lymphocytes are introduced into an 
allogeneic recipient whose immune system is compromised. The grafted lymphocytes begin to 
attack the recipient and the recipient's compromised state prevents an immune response against 
the graft. The grafted lymphocytes are carried to the spleen, where they begin to proliferate in 
response to the allogeneic MHC antigens of the recipient. This proliferation induces an influx 
of recipient cells to the spleen and results in splenomegaly. The intensity of GVHD can be 
quantitated by calculating the spleen index (SI). A spleen index of 1.3 or greater is considered to 
be indicative of GVHD. Enlargement of the spleen is a result of proliferation of both CD4 + and 
CD8 + T-cell populations^-- 



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-^DTH plays an important role in host defense against intracellular pathogens. A 
variety of pathogens and contact antibodies can induce a DTH response. The initial immune 
response is nonspecific and often results in significant damage to healthy tissue. Although 
healthy tissue can be damaged, the patient can successfully eliminate cells infected by 
intracellular pathogens. When this defense process is not entirely effective, the continued 
presence of the pathogen's antigens can provoke a chronic DTH reaction. The chronic DTH 
reaction is characterized by excessive numbers of macrophages and the continued release of lytic 
enzymes resulting in tissue destruction. Thus, the DTH response to an intracellular pathogen can 
cause such extensive tissue damage that the DTH response is a pathologic condition. The 
granulomatous skin lesion seen with Mycobacterium leprae and the lung cavitation seen with 
Mycobacterium tuberculosis infections are examples of such pathology resulting from a chronic 
DTH reaction. Chronic DTH responses can result in granulomatous disease^f^- 



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^- Murine Model for Graft -Versus-Host Disease d