Methods of treating HIV infected subjects
Methods for inducing a population of T cells to proliferate by activating the population of T cells and stimulating an accessory molecule on the surface of the T cells with a ligand which binds the accessory molecule are described. T cell proliferation occurs in the absence of exogenous growth factors or accessory cells. T cell activation is accomplished by stimulating the T cell receptor (TCR)/CD3 complex or the CD2 surface protein. To induce proliferation of an activated population T cells, an accessory molecule on the surface of the T cells, such as CD28, is stimulated with a ligand which binds the accessory molecule. The T cell population expanded by the method of the invention can be genetically transduced and used for immunotherapy or can be used in methods of diagnosis.
1. A method for inducing ex vivo proliferation of a population of T cells from an HIV-infected subject to sufficient numbers for use in therapy, comprising contacting a population of T cells ex vivo with a surface having attached thereto:
an anti-CD3 antibody or CD3-binding fragment thereof, which stimulates a TCR/CD3 complex-associated signal in T cells, and
an anti-CD28 antibody or CD28-binding fragment thereof, which stimulates a CD28-sssociated signal in T cells;
wherein the anti-CD3 antibody or CD3-binding fragment thereof, and the anli-CD28 antibody or CD28-binding fragment thereof, are attached on the same surface,
the anti-CD3 antibody or CD3-binding fragment thereof and the anti-CD28 antibody or CD28-binding fragment thereof thereby, inducing the T cells to proliferate to sufficient numbers for use in therapy; and
whereby the CD28 stimulation by the anti-CD28 antibody or CD28-binding fragment thereof provides a proliferative advantage for HIV-uninfected CD4 + T cells over HIV-infected CD4 + T cells and a protective effect against HIV infection for uninfected CD4 + T cells.
2. A method for inducing ex vivo proliferation of a population of T cells from an HIV-infected subject to sufficient numbers for use in therapy, comprising contacting a population of T cells ex vivo with a surface having attached thereto:
an anti-CD3 antibody or CD3-binding fragment thereof, which stimulates a TCR/CD3 complex-associated signal in T cells, and
an anti-CD28 antibody or CD28-binding fragment thereof, which stimulates a CD28-sssociated signal in T cells;
wherein the anti-CD3 antibody or CD3-binding fragment thereof, and the anti-CD28 antibody or CD28-binding fragment thereof, are attached on the same surface,
the anti-CD3 antibody or CD3-binding fragment thereof, and the anti-CD28 antibody or CD28-binding fragment thereof, thereby inducing the T cells to proliferate to sufficient numbers for use in therapy; and
whereby the percent CD4 + T cells expressing the cell surface marker CD45RO increases.
3. A method of treating an HIV-infected subject, comprising contacting a population of T cells from the subject ex vivo with a surface having attached thereto:
an anti-CD3 antibody or CD3-binding fragment thereof, which stimulates a TCR/CD3 complex-associated signal in T cells, and
an anti-CD28 antibody or CD28-binding fragment thereof, which stimulates a CD28-sssociated signal in T cells;
wherein the anti-CD3 antibody or CD3-binding fragment thereof, and the anti-CD28 antibody or CD28-binding fragment thereof, are attached on the same surface,
the anti-CD3 antibody or CD3-binding fragment thereof, and the anti-CD28 antibody or CD28-binding fragment thereof, thereby inducing the T cells to proliferate to sufficient numbers for use in therapy;
whereby the CD28 stimulation by the anti-CD28 antibody or CD28-binding fragment thereof provides a proliferative advantage for HIV-iminfected CD4 + T cells over HIV-infected CD4 + T cells and a protective effect against HIV infection for uninfected CD4 + T cells, and readministering the T cells to the subject.
4. A method of treating an HIV-infected subject, comprising contacting a population of T cells from the subject ex vivo with a surface having attached thereto:
an anti-CD3 antibody or CD3-binding fragment thereof, which stimulates a TCR/CD3 complex-associated signal in T cells, and
an anti-CD28 antibody or CD28-binding fragment thereof, which stimulates a CD28-sssociated signal in T cells;
wherein the anti-CD3 antibody or CD3-binding fragment thereof, and the anti-CD28 antibody or CD28-binding fragment thereof, are attached on the same surface,
the anti-CD3 antibody or CD3-binding fragment thereof, and the anti-CD28 antibody or CD28-binding fragment thereof, thereby inducing the T cells to proliferate to sufficient numbers for use in therapy;
whereby the percent of CD4 + T cells expressing the cell surface marker CD45RO increases, and readministering the T cells to the subject.
5. The method of any one of claims 1 , 2 , 3 , or 4 , wherein the anti-CD3 antibody or CD3-binding fragment thereof is an anti-human CD3 antibody or CD3-binding fragment thereof.
6. The method of any one of claims 1 , 2 , 3 , or 4 , wherein the anti-CD28 antibody or CD28-binding fragment thereof is an anti-human CD28 antibody or CD28-binding fragment thereof.
7. The method of any one of claims 1 , 2 , 3 , or 4 , further comprising contacting said population of T cells ex vivo with IL-2.
8. The method of any one of claims 1 , 5 , 7 , 2 , 3 , or 4 , wherein the anti-CD3 antibody or CD3-binding fragment thereof, and the anti-CD28 antibody or CD28-binding fragment thereof, are monoclonal antibodies or fragments thereof.
9. The method of any one of claims 1 , 2 , 3 , or 4 , further comprising contacting said population of T cells ex vivo with an anti-retroviral agent.
10. The method of any one of claims 1 or 2 , further comprising re-administering said population of T cells to said subject.
11. The method of any one of claims 1 , 2 , 3 , or 4 , wherein said surface is a bead.
12. The method of any one of claims 1 , 2 , 3 , or 4 , wherein said surface is a magnetic immunobead.
13. The method of any one of claims 1 , 2 , 3 , or 4 , wherein said surface is a tissue culture dish.
14. The method of any one of claims 1 , 2 , 3 , or 4 , wherein said surface is a cell surface.