Reducing Systemic Regulatory T Cell Levels or Activity for Treatment of Disease and Injury of the CNS

1 . A method of treating a neurodegenerative disease to an individual in need thereof, the method comprising administering to the individual a composition comprising an anti-CD40 antibody, an anti-CD40L antibody, or any combination thereof;

wherein the neurodegenerative disease is an amyotrophic lateral sclerosis or an Alzheimer's disease;

wherein the composition is administered by a dosage regime comprising at least two courses of therapy, each course of therapy comprising in sequence a treatment session where the composition is administered to the individual followed by a non-treatment period where the composition is not administered to the individual,

wherein the non-treatment period is longer than the treatment session;

wherein, if administration of the composition during the treatment session is a repeated administration, the non-treatment period is longer than the period between repeated administrations during the treatment session;

wherein administration of the composition transiently reduces levels of systemic immunosuppression and increases choroid plexus gateway activity in facilitating selective recruitment of immune cells into the central nervous system, thereby treating the individual.

2 . The method according to claim 1 , wherein the administration of the composition during the treatment session is a single administration or a repeated administration.

3 . The method according to claim 2 , wherein the repeated administration occurs once weekly or once every two weeks, once every three weeks or once every four weeks.

4 . The method according to claim 3 , wherein the treatment session is from one week to four weeks.

5 . The method according to claim 1 , wherein the non-treatment period is 14 days or longer.

6 . The method according to claim 5 , wherein the non-treatment period is one month or longer.

7 . The method according to claim 5 , wherein the non-treatment period is from three weeks to six months.

8 . The method according to claim 7 , wherein the non-treatment period is from one month to three months.

9 . The method according to claim 1 , wherein the anti-CD40 antibody or the anti-CD40 antibody is a polyclonal antibody or a monoclonal antibody, or wherein both the anti-CD40 antibody and the anti-CD40 antibody are a polyclonal antibody or a monoclonal antibody.

10 . The method according to claim 1 , wherein the anti-CD40 antibody or the anti-CD40 antibody is a dimer, a multimer, a multispecific antibody, a recombinant antibody, a chimeric antibody, bi-functional antibody, a cell-associated antibody like an Ig receptor, a linear antibody, a diabody, a minibody or a nanobody; or wherein both the anti-CD40 antibody and the anti-CD40 antibody are a dimer, a multimer, a multispecific antibody, a recombinant antibody, a chimeric antibody, bi-functional antibody, a cell-associated antibody like an Ig receptor, a linear antibody, a diabody, a minibody or a nanobody.

11 . The method according to claim 1 , wherein the anti-CD40 antibody or the anti-CD40 antibody is a human anti-CD40 antibody or a humanized anti-CD40 antibody; or wherein the anti-CD40 antibody and the anti-CD40 antibody is a human anti-CD40 antibody or a humanized anti-CD40 antibody.

12 . The method according to claim 1 , wherein the transient reduction in the level of systemic immunosuppression is associated with an increase in a systemic presence or activity of IFNγ-producing leukocytes and/or an increase in a systemic presence or activity of an IFNγ cytokine, an increase in a systemic presence or activity of effector T cells, a decrease in a systemic presence or activity of regulatory T cells and/or a decrease in a systemic presence of an IL-10 cytokine, and/or a decrease in a systemic presence or myeloid-derived suppressor cells (MDSCs).

13 . The method according to claim 1 , wherein the transient reduction in the level of systemic immunosuppression occurs by release of a restraint imposed on the immune system by one or more immune checkpoints.

14 . The method according to claim 13 , wherein administration of the composition blocks the one or more immune checkpoints, thereby causing the transient reduction in the level of systemic immunosuppression.

15 . The method according to claim 14 , wherein the one or more immune checkpoints includes a CD40L-CD40 immune checkpoint.

16 . The method according to claim 1 , wherein treating the individual improves a motor neurological function.

17 . The method according to claim 16 , wherein the motor neurological function includes a motor muscle function, a movement coordination function, a maintenance of balance or equilibrium and/or an autonomic function.

18 . The method according to claim 1 , wherein a cerebral level of soluble amyloid beta peptide is reduced in the individual, a cerebral amyloid beta (Aβ) plaque burden is reduced or cleared in the individual, a hippocampal gliosis is reduced in the individual, a cerebral level of a pro-inflammatory cytokine is reduced in the individual, a brain inflammation is decreased in the individual and/or a cognitive function is improved in the individual.

19 . The method according to claim 18 , wherein the improved cognitive function is learning, memory, creation of imagery, plasticity, thinking, awareness, reasoning, spatial ability, speech and language skills, language acquisition, capacity for judgment attention or any combination thereof.

20 . The method according to claim 1 , wherein the immune cells include monocytes, monocyte-derived macrophages, or immunoregulatory T cells.

21 . The method according to claim 1 , wherein the anti-CD40L antibody is a bi-functional, single-chain variable fragment (scFv), F(ab′)2 antibody fragment.

22 . The method according to claim 1 , wherein the anti-CD40L antibody is a multispecific, single-chain variable fragment (scFv), F(ab′)2 antibody fragment.