Modulation of pathogenic CD14+/CD16+ monocytes
The invention is based on the discovery that interleukin-1 alpha (IL-1alpha) is expressed on the proinflammatory CD14+CD16+ monocyte subset. Importantly, since IL-1alpha appears to be almost exclusively expressed on this monocyte subset and not other leukocytes, it represents an ideal marker for targeting the CD14+CD16+ monocyte subset. The effectiveness of an agent that depletes such pathogenic cells or modulates IL-1alpha function on such cells type can be monitored by assessing CD14+CD16+ monocyte levels or functionality.
1. A method comprising the steps of:
(a) determining that a human subject with a disease or pathologic disorder has high levels of CD14+/CD16+ monocytes that contribute to the disease or pathologic disorder by removing a first sample of peripheral blood from the subject and performing flow cytometry on cells comprised within the first sample to assess the number or percent of CD14+/CD16+ monocytes in the first sample;
(b) administering an agent that modulates the function or expression of interleukin-lalpha to the human subject; and
(c) determining whether such administration modulates the amount of CD14+CD16+ monocytes in the subject by removing a second sample of peripheral blood mononuclear cells from the subject and performing flow cytometry on cells comprised within the second sample to assess the number or percent of CD14+/CD16+ monocytes in the second sample.
2. The method of claim 1 , wherein the agent that modulates the function or expression of interleukin-1 alpha is one that interferes with interleukin-1 alpha binding to an interleukin-1 alpha receptor.
3. The method of claim 1 , wherein the agent is an antibody that specifically binds interleukin-1 alpha.
4. The method of claim 3 , wherein the antibody is a monoclonal antibody that specifically binds interleukin-1 alpha.
5. The method of claim 4 , wherein the monoclonal antibody is a human antibody.
6. The method of claim 5 , wherein the human antibody is an IgG1.
7. The method of claim 6 , wherein the human antibody has a heavy chain comprising the amino acid sequence of SEQ ID NO:3 and a light chain comprising the amino acid sequence of SEQ ID NO:4.
8. The method of claim 1 , wherein the human subject has a pathology associated with aberrant function or levels of CD14+CD16+ monocytes.
9. The method of claim 8 , wherein the disease or pathologic disorder is an inflammatory condition.
10. The method of claim 8 , wherein the disease or pathologic disorder is an autoimmune condition.
11. The method of claim 1 , wherein at least 1.5% of the human subject's peripheral blood leukocytes are CD14+CD16+ monocytes before administration of the agent and less than 1.5% of the human subject's peripheral blood leukocytes cells are CD14+CD16+ monocytes after administration of the agent.
12. The method of claim 1 , wherein administration of the agent results in at least a 10% reduction in the percent of CD14+CD16+ monocytes in a complete blood count with differential.
13. The method of claim 1 , wherein the step of determining whether such administration modulates the amount or function of CD14+CD16+ monocytes in the subject comprises assessing the function of the subject's CD14+CD16+ monocytes before and after administration of the agent.
14. The method of claim 13 , wherein administration of the agent results in at least a 10% reduction in the function of CD14+CD16+ monocytes.