Methods of transplantation and disease treatment

1. A method of transplantation, the method comprising administering to a subject in need of transplantation of cells in suspension, a therapeutically effective amount of tolerance inducing anti-third party cytotoxic T-lymphocytes (CTLs), wherein said tolerance inducing anti-third party CTLs are generated by directing T-lymphocytes of a donor against a third party antigen or antigens, said tolerance inducing anti-third party CTLs being substantially depleted of T-lymphocytes capable of developing into alloreactive CTLs, and wherein said tolerance inducing anti-third party CTLs do not comprise cells having a central memory T-lymphocyte (Tcm) phenotype, wherein said cells in suspension comprise non-hematopoietic cells or hematopoietic cells which are not stem cells.

2. A method of treating a disease in a subject in need thereof, the method comprising:

(a) administering to the subject a therapeutically effective amount of cells in suspension, wherein said cells in suspension comprise non-hematopoietic cells or hematopoietic cells which are not stem cells; and

(b) administering to said subject a therapeutically effective amount of tolerance inducing anti-third party cytotoxic T-lymphocytes (CTLs), wherein said tolerance inducing anti-third party CTLs are generated by directing T-lymphocytes of a donor against a third party antigen or antigens, said tolerance inducing anti-third party CTLs being substantially depleted of T-lymphocytes capable of developing into alloreactive CTLs, and wherein said tolerance inducing anti-third party CTLs do not comprise cells having a central memory T-lymphocyte (Tcm) phenotype, thereby treating the disease.

3. The method of claim 2 , wherein step (a) and step (b) are carried out concomitantly.

4. The method of claim 2 , wherein step (b) is carried out prior to step (a).

5. The method of claim 1 , further comprising administering said cells in suspension to the subject.

6. The method of claim 1 , wherein said non-hematopoietic cells comprise differentiated cells, or progenitor or stem cells.

7. The method of claim 6 , wherein said differentiated cells:

are selected from the group consisting of pulmonary cells, pancreatic cells, nephric cells, hepatic cells, cardiac cells, brain cells, intestine cells, skin cells, spleen cells and ovarian cells; or

are obtained from a fetal tissue; or

are obtained from an adult tissue.

8. The method of claim 6 , wherein said progenitor cells or stem cells are selected from the group consisting of mesenchymal stem cells, endothelial progenitor cells and epithelial progenitor cells.

9. The method of claim 1 , wherein said hematopoietic cells which are not stem cells comprise a subpopulation of lymphatic cells or immune cells.

10. The method of claim 9 , wherein said immune cells are selected from the group consisting of T cells, B cells, NK cells, NKT cells and dendritic cells (DCs).

11. The method of claim 10 , wherein said T cells are selected from the group consisting of CD4+ T cells, CD8+ T cells, tumor infiltrating lymphocytes (TIL) and tumor-associated lymphocytes (TALs).

12. The method of claim 1 , wherein said non-hematopoietic cells or hematopoietic cells which are not stem cells are genetically modified.

13. The method of claim 12 , wherein said genetically modified cells comprise genetically modified immune cells.

14. The method of claim 13 , wherein said immune cells express a chimeric antigen receptor (CAR) or a modified T cell receptor (TCR).

15. The method of claim 14 , wherein said immune cells are T cells.

16. The method of claim 1 , wherein said administering to said subject a therapeutically effective amount of said tolerance inducing anti-third party CTLs, is effected at least twice.

17. The method of claim 8 , wherein:

when the progenitor cells are mesenchymal stem cells the disease is a medical condition selected from the group consisting of a cosmetic condition, a tissue or organ damage, an orthopedic condition, a neural condition, a heart disease or condition, a diabetes, a deafness, a Crohn's disease, an autoimmune disorder, a leukemia, a cancer, a sickle cell disease, an amyotrophic lateral sclerosis and a metabolic disorders; or

when the progenitor cells are endothelial progenitor cells the disease is a medical condition selected from the group consisting of a bone disease, a bone damage, a cardiovascular disease, a cardiovascular injury, an ischemic disease, an ischemic injury, a vascular disease, a sickle cell disease, an atherosclerosis, a diabetes and an autoimmune disorder; or

when the progenitor cells are epithelial progenitor cells the disease is a medical condition selected from the group consisting of a ulcer, an inflammatory bowel disease (IBD), a Crohn's disease, an ulcerative colitis, an Alzheimer's disease, a wound healing defect, a cancer, a chronic obstructive pulmonary disease (COPD), a pulmonary fibrosis, an idiopatic pulmonary fibrosis, a pulmonary hypertension, a lung cancer, a sarcoidosis, an acute lung injury (adult respiratory distress syndrome), a respiratory distress syndrome of prematurity, a chronic lung disease of prematurity (bronchopulmonary dysplasia), a surfactant protein B deficiency, a congenital diaphragmatic hernia, a pulmonary alveolar proteinosis, a pulmonary hypoplasia, a lung injury and a corneal degeneration.

18. The method of claim 9 , wherein when the hematopoietic cells which are not stem cells comprise immune cells the disease is a medical condition selected from the group consisting of a malignancy, an autoimmune disease and an infectious disease.

19. The method of claim 1 , wherein said non-hematopoietic cells or hematopoietic cells which are not stem cells are non-syngeneic with the subject.

20. The method of claim 1 , wherein said non-hematopoietic cells or hematopoietic cells which are not stem cells and said tolerance inducing anti-third party CTLs are obtained from the same donor.

21. The method of claim 1 , wherein said tolerance inducing anti-third party CTLs are non-syngeneic with the subject.

22. The method of claim 1 , wherein said cells having a Tcm phenotype:

are capable of homing to the lymph nodes following transplantation; and/or

comprise a CD3 + , CD8 + , CD62L + , CD45RA − , CD45RO + signature.

23. The method of claim 1 , wherein said tolerance inducing anti-third party CTLs are substantially depleted of CD4+ T cells and/or CD56+ natural killer cells.

24. The method of claim 1 , wherein said tolerance inducing anti-third party CTLs comprise a CD3+ CD8+ phenotype.

25. The method of claim 1 , wherein depletion of said T-lymphocytes capable of developing into said alloreactive CTLs is effected by deprivation of a factor which is (i) required for CTL maturation; and (ii) secreted by maturing CTLs.

26. The method of claim 25 , wherein said deprivation of a factor is effected for 3-10 days.

27. The method of claim 25 , wherein said factor is a cytokine.

28. The method of claim 27 , wherein said cytokine is IL-2.

29. The method of claim 1 , wherein said tolerance inducing anti-third party CTLs being substantially depleted of T-lymphocytes capable of developing into alloreactive CTLs are generated by a method comprising:

(a) directing T-lymphocytes of a donor against a third party antigen or antigens in a culture deprived of IL-2 so as to deplete alloreactive CTLs; and

(b) contacting said CTLs of step (a) with a third party antigen or antigens in the presence of IL-2 so as to allow enrichment of said tolerance inducing anti-third party CTLs.

30. The method of claim 29 , further comprising depleting CD4+ T cells and/or CD56+ natural killer cells following step (a) and prior to step (b).

31. The method of claim 29 , further comprising selecting for CD8+ T cells following step (a) and prior to step (b).

32. The method of claim 1 , wherein depletion of T-lymphocytes capable of developing into said alloreactive CTLs is effected by affinity labeling followed by label based separation.

33. The method of claim 1 , wherein depletion of T-lymphocytes capable of developing into alloreactive CTLs is effected by affinity purification.

34. The method of claim 1 , further comprising conditioning the subject under sublethal, lethal or supralethal conditioning protocol prior to said administering.

35. The method of claim 34 , wherein said sublethal, lethal or supralethal conditioning is selected from the group consisting of a total body irradiation (TBI), a partial body irradiation, a myeloablative conditioning, a non-myeloablative conditioning, a co-stimulatory blockade, a chemotherapeutic agent and an antibody immunotherapy.

36. The method of claim 1 , wherein said subject is a human subject.

37. The method of claim 1 , wherein said third party antigen or antigens comprise dendritic cells.

38. The method of claim 1 , wherein said third party antigen or antigens is selected from the group consisting of third party cells, a cell antigen, a viral antigen, a bacterial antigen, a protein extract, a purified protein and a synthetic peptide presented by autologous presenting cells, non-autologous presenting cells or on an artificial vehicle or on artificial antigen presenting cells.

39. The method of claim 38 , wherein said third party cells are stimulatory cells selected from the group consisting of cells purified from peripheral blood lymphocytes, spleen or lymph nodes, cytokine-mobilized PBLs, in vitro expanded antigen-presenting cells (APC), in vitro expanded dendritic cells and artificial antigen presenting cells.