I claim:
1. A method for inducing donor-specific tolerance andor mixed donor-recipient chimerism in an allograft transplant recipient, comprising the steps of:
(a) administering to a recipient of an allograft a therapeutically effective amount of an immunosuppressive agent that depletes T cells;
(b) administering to the recipient of the allograft a therapeutically effective amount of anti- T cell receptor antibodies;
(c) implanting an allograft from an allograft donor into the recipient; and
(d) implanting a therapeutically effective amount of bone marrow cells from the allograft donor into the allograft recipient.
2. The method of claim 1, wherein the steps of administering the immunosuppressive agent and the anti- T cell receptor antibodies, and implanting of the donor bone marrow cells, results in induction of hematopoietic mixed donor-recipient chimerism in the recipient.
3. The method of claim 1, wherein the therapeutically effective amount of allograft donor bone marrow cells is an amount sufficient to induce the production of mixed donor-recipient chimerism in the recipient.
4. The method of claim 3, wherein the mixed donor-recipient chimerism in the recipient comprises a level of mixed donor and recipient cells of about 5% to about 50% of circulating peripheral blood mononuclear cells.
5. The method of claim 4, wherein the level of mixed donor and recipient cells is about 10% to about 40% of circulating peripheral blood mononuclear cells.
6. The method of claim 5, wherein the level of mixed donor and recipient cells is about 20% to about 30% of circulating peripheral blood mononuclear cells.
7. The method of claim 1, wherein the therapeutically effective amount of the allograft donor bone marrow cells is an amount sufficient to maintain long-term recipient tolerance of the allograft without readministration of the immunosuppressive agent and the anti- T cell receptor antibodies.
8. The method of claim 1, wherein the step of implanting bone marrow cells comprises the substeps of implanting and vascularizing an allograft donor bone including the bone marrow into the recipient.
9. The method of claim 8, wherein the allograft donor bone further includes an attached portion of donor skin, and wherein the substeps of implanting and vascularizing the donor bone into the recipient further includes the substeps of implanting and vascularizing the attached portion of donor skin.
10. The method of claim 1, wherein the step of implanting bone marrow cells comprises the substeps of obtaining crude bone marrow from a bone of the allograft donor, and implanting the donor crude bone marrow into the allograft recipient.
11. The method of claim 10, wherein the substep of implanting the allograft donor crude bone marrow further comprises the substeps of removing a quantity of crude bone marrow from a recipient bone marrow compartment to provide a space in the compartment, and directly implanting the allograft donor crude bone marrow into the space.
12. The method of claim 1, wherein the step of implanting bone marrow cells comprises the substeps of obtaining a bone marrow nucleated cell suspension from a bone of the allograft donor, and implanting the bone marrow nucleated cell suspension into the recipient.
13. The method of claim 12, wherein the bone marrow cell suspension is implanted by direct intraosseous injection of the suspension into a recipient bone.
14. The method of claim 12, wherein the bone marrow nucleated cell suspension is implanted by intravenous injection into the recipient.
15. The method of claim 1, wherein the step of implanting bone marrow cells comprises the substeps of obtaining a bone marrow cell suspension from a bone of the allograft donor; isolating a nucleated subpopulation of the bone marrow cells, and implanting the nucleated subpopulation of the bone marrow cells into the recipient.
16. The method of claim 15, wherein the subpopulation of the bone marrow cells is implanted by direct intraosseous injection of the suspension into a recipient bone.
17. The method of claim 15, wherein the subpopulation of the bone marrow cells is implanted by intravenous injection of the suspension into the recipient.
18. The method of claim 15, wherein the subpopulation of the isolated bone marrow cells includes tolerance inducing cells.
19. The method of claim 15, wherein the subpopulation of the isolated bone marrow cells includes CD4 cells.
20. The method of claim 15, wherein the subpopulation of the isolated bone marrow cells includes CD8 cells.
21. The method of claim 15, wherein the subpopulation of the isolated bone marrow cells includes hematopoietic stem cells.
22. The method of claim 15, wherein the subpopulation of the isolated bone marrow cells includes hematopoietic progenitor cells.
23. The method of claim 1, wherein the immunosuppressive agent and the anti- T cell receptor antibodies are administered in an amount, at a frequency, and for a duration of time sufficient to eliminate about 50% to about 99.9% of recipient T cells circulating in peripheral blood of the recipient.
24. The method of claim 1, wherein the immunosuppressive agent comprises an IL-2 production inhibitor.
25. The method of claim 1, wherein the immunosuppressive agent comprises a calcineurin inhibitor.
26. The method of claim 1, wherein the immunosuppressive agent is selected from the group consisting of cyclosporine A, FK-506, rapamycin, and combinations thereof.
27. The method of claim 1, wherein the allograft is selected from the group consisting of composite tissue, solid organs, glands, glandular cells, skin, hematopoietic tissue, lymphoid tissue, tendons, ligaments, muscles, nerve tissue, vascular tissue and combinations thereof.
28. The method of claim 1, wherein the step of implanting the allograft does not include recipient preconditioning.
29. The method of claim 1, wherein the allograft recipient is a human.
30. The method of claim 29, wherein the anti- TCR receptor antibodies are human antibodies to human TCR T cells.
31. The method of claim 29, wherein the anti- TCR receptor antibodies are humanized monoclonal antibodies to human TCR T cells.
32. The method of claim 29, wherein the anti- TCR receptor antibodies are human monoclonal antibodies to human TCR T cells.
33. The method of claim 1, wherein the anti- TCR receptor antibodies are monoclonal antibodies.
34. A method for inducing donor-specific tolerance andor mixed donor-recipient trimerism in an allograft transplant recipient, comprising the steps of:
(a) administering to a recipient of an allograft a therapeutically effective amount of an immunosuppressive agent that depletes T cells;
(b) administering to the recipient of the allograft a therapeutically effective amount of anti- T cell receptor antibodies;
(c) implanting a first allograft from a first allogeneic allograft donor into the recipient;
(d) implanting a therapeutically effective amount of bone marrow cells from the first allograft donor into the recipient.
(e) implanting a second allograft from a second allogeneic allograft donor into the recipient; and
(f) implanting a therapeutically effective amount of bone marrow cells from the second allograft donor into the allograft recipient,
wherein a state of trimerism is induced in the recipient.
35. The method of claim 34, wherein the first and second allogeneic allograft donors are independently selected from semi-allogeneic donors; fully allogeneic donors; and
combinations thereof, with respect to the recipient.
36. The method of claim 34, wherein the state of trimerism in the recipient comprises a level of mixed donor and recipient cells of about 0.1% to about 15% of circulating peripheral blood mononuclear cells.
37. The method of claim 34, wherein the state of trimerism in the recipient comprises a level of mixed donor and recipient cells of about 1% to about 10% of circulating peripheral blood mononuclear cells.
38. A method for monitoring allograft rejection in an allograft transplant recipient, comprising the steps of:
(a) administering to a recipient of an allograft a therapeutically effective amount of an immunosuppressive agent that depletes T cells;
(b) administering to the recipient of the allograft a therapeutically effective amount of anti- T cell receptor antibodies;
(c) implanting an allograft from a donor into the recipient;
(d) implanting a therapeutically effective amount of bone marrow cells from the allograft donor into the recipient; and
(e) implanting an additional allograft from the donor into the recipient for monitoring allograft rejection in the recipient.
39. The method of claim 38, wherein the additional allograft is vascularized in the recipient.
40. The method of claim 39, wherein the additional allograft is skin.
41. The method of claim 38, wherein the additional allograft is unvascularized in the recipient.
42. The method of claim 41, wherein the additional allograft is skin.
43. The method of claim 38, wherein the allograft is selected from the group consisting of composite tissue, solid organs, glands, glandular cells, skin, hematopoietic tissue, lymphoid tissue, tendons, ligaments, muscles, nerve tissue, vascular tissue and combinations thereof.
44. A system for inducing donor-specific tolerance andor mixed donor-recipient chimerism in an allograft transplant recipient, comprising:
(a) a combination of pharmaceutical compositions for depletion of T cells in a recipient of an allograft from a donor, comprising an effective amount of a pharmaceutical composition that comprises an immunosuppressive T cell-depleting agent, and an effective amount of a pharmaceutical composition that comprises anti- TCR T cell receptor antibodies, wherein administration of the combination to the recipient results in elimination of about 50% to about 99.9% of T cells circulating in peripheral blood of the recipient;
(b) a delivery system for implanting a therapeutically effective amount of bone marrow cells from the allograft donor into the allograft recipient, wherein the delivery system is selected from the group consisting of an implantable vascularizable bone from the allograft donor including the donor bone marrow; implantable crude donor bone marrow; an implantable donor bone marrow nucleated cell suspension; an implantable isolated subpopulation of donor bone marrow cells; and combinations thereof.
45. The system of claim 44 wherein the implantable isolated subpopulation of bone marrow cells is selected from the group consisting of tolerance inducing cells, hematopoietic stem cells, hematopoietic progenitor cells, CD4 cells, CD8 cells, and combinations thereof.
46. The system of claim 44 wherein the effective amount of the combination of pharmaceutical compositions is sufficient to eliminate about 75% to about 95% of circulating T cells.
47. The system of claim 46 wherein the effective amount of the combination is sufficient to eliminate about 80% to about 90% of circulating T cells.
48. The system of claim 44 wherein the immunosuppressive agent comprises an IL-2 production inhibitor.
49. The system of claim 44, wherein the immunosuppressive agent comprises a calcineurin inhibitor.
50. The system of claim 44, wherein the immunosuppressive agent is selected from the group consisting of cyclosporine A, FK-506, rapamycin, and combinations thereof.
51. The system of claim 50, wherein the immunosuppressive agent comprises cyclosporine A.
52. The system of claim 44, wherein the recipient is a human.
53. The system of claim 52, wherein the anti- TCR receptor antibodies are human antibodies to human TCR T cells.
54. The system of claim 52, wherein the anti- TCR receptor antibodies are humanized monoclonal antibodies to human TCR T cells.
55. The system of claim 52, wherein the anti- TCR receptor antibodies are human monoclonal antibodies to human TCR T cells.
56. The system of claim 44, wherein the anti- TCR receptor antibodies are monoclonal antibodies.
57. A method for maintaining a level of mixed donor-recipient chimerism in an allograft transplant recipient, comprising the steps of:
(a) inducing donor-specific tolerance andor mixed donor-recipient chimerism in an allograft recipient by (i) administering to a recipient of an allograft a therapeutically effective amount of an immunosuppressive agent that depletes T cells; (ii) administering to the recipient of the allograft a therapeutically effective amount of anti- T cell receptor antibodies; (iii) implanting an allograft from an allograft donor into the recipient; and (iv) implanting a therapeutically effective amount of bone marrow cells from the allograft donor into the allograft recipient;
(b) determining an optimal level of chimeric cells in the recipient not undergoing rejection of the allograft;
(c) harvesting chimeric cells from the recipient when the optimal level of chimeric cells is achieved;
(d) reconstituting the recipient with the harvested chimeric cells when the level of chimeric cells in the recipient falls below a minimum level of chimeric cells; and
(e) optionally readministering an effective amount of the immunosuppressive agent andor the anti- T cell receptor antibodies.
58. The method of claim 57, wherein the step of reconstituting the recipient comprises administering the chimeric cells by a method selected from the group consisting of direct intraosseous injection into a recipient bone marrow cavity; direct intraosseous injection into a bone marrow cavity of an implanted donor bone allograft; intravenous injection into the recipient; and combinations thereof.
59. The method of claim 57, wherein the minimum level of chimeric cells is about 5% to about 20% of circulating peripheral blood mononuclear cells.
60. The method of claim 57, wherein the optimal level of chimeric cells is about 10% to about 50% of circulating peripheral blood mononuclear cells.
61. The method of claim 60, wherein the optimal level of chimeric cells is about 20% to about 30% of circulating peripheral blood mononuclear cells.
62. The method of claim 57, wherein the harvesting step comprises isolating chimeric cells from the peripheral blood of the recipient.
63. The method of claim 57, wherein the harvesting step includes the substeps of isolating peripheral blood mononuclear cells from the recipient and, optionally, isolating chimeric cells from the isolated peripheral blood mononuclear cells.
64. The method of claim 57, wherein the harvesting step includes the substep of propagating the chimeric cells in culture prior to the reconstituting step.
65. The method of claim 57, wherein the harvesting step includes the substep of storing the chimeric cells prior to the reconstituting step.
66. The method of claim 65, wherein the substep of storing the chimeric cells comprises storing the cells at 196 C. in liquid nitrogen.
67. The method of claim 57, wherein the reconstituting step includes the step of obtaining a portion of the harvested chimeric cells and reconstituting the recipient with the portion.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. Method for automatically adapting a write cycle to a movement of a web-shaped medium in a digital printing machine during operation of the machine, as a function of a thickness (T) of the web-shaped medium, the method comprising:
providing a first transport or guide roller having a first known diameter (DU) and a second transport or guide roller having a known second diameter (DT), the second diameter being different from the first diameter (DU) wherein the web-shaped medium (6) is guided around the first transport or guide roller and the second transport or guide roller;
determining a rotational speed ratio N(T) between the first and the second transport or guide rollers while the web-shaped medium is guided around the transport or guide rollers; and
determining the write cycle at least with the use of the previously determined rotational speed ratio N(T).
2. The method according to claim 1, wherein, the write-cycle-determining step includes first determining a nominal write cycle based on a rotational speed of the second transport or guide roller and on a previously mathematically- or experimentally-determined scaling factor KN that correlates to a nominal thickness of the printing material, and subsequently adapting the nominal write cycle using the determined rotational speed ratio N(T).
3. The method according to claim 1, further including determining a nominal rotational speed ratio NN and using the determined ratio in the determination of the write cycle, namely mathematically, using a known nominal thickness of the web-shaped medium, the diameter (DU) of the first transport or guide roller and the diameter (DT) of the second transport or guide roller.
4. The method according to claim 3, further including, during operation, determining an adaptation value K(T) using the nominal rotational speed ratio (NN) and the determined rotational speed ratio N(T), and adapting the nominal write cycle using the adaptation value.
5. The method according to claim 1, wherein the rotational-speed-ratio determining step includes:
delivering to a counter the first pulses of a first encoder that is connected to the first transport or guide roller and the second pulses of a second encoder that is connected to the second transport or guide roller, each of the second pulses incrementing the value of the counter and the first pulses resetting the counter;
determining the value of the counter between each two successive pulses of the first encoder; and
using the detected values of the counter, a number of bars P1 of the first encoder, and a number of bars P2 of the second encoder to determine the rotational speed ratio N(T).
6. The method according to claim 5, wherein the number of bars P2 of the second encoder is selected as a function of the diameter of the second transport or guide roller so that the pulses of the second encoder enable a higher local resolution than a highest desired line resolution of an image that is to be printed.
7. The method according to claim 6, further including low-pass-filtering the detected values of the counter through a sliding mean-value determination.
8. The method according to claim 5, further including low-pass-filtering the detected values of the counter through a sliding mean-value determination.
9. A device for automatically adapting a write cycle to a movement of a web-shaped medium in a digital printing machine as a function of a thickness of the web-shaped medium, the device comprising:
a first transport or guide roller having a known first diameter (DU), the transport or guide roller being connected to a first encoder;
a second transport or guide roller having a known second diameter (DT) that is different from the first diameter (DU), the roller being connected to a second encoder, the web-shaped medium being guided around the first and second transport or guide rollers; and
a control unit that is capable of receiving pulses from the first and the second encoders and of determining, from the pulses, a ratio of rotational speeds between the first and the second transport or guide rollers during operation, and of performing an adaptation of the write cycle at least with the use of the determined ratio of rotational speeds.
10. The device according to claim 9, wherein the control device includes a counter, the second encoder is connected to the incremental input of the counter, and the first encoder is connected to a reset input of the counter.
11. The device according to claim 9, wherein the second encoder has a number of bars that is selected as a function of the diameter of the second transport or guide roller in such a manner that a local resolution higher than the highest desired line resolution of an image to be printed can be achieved.
12. The device according to claim 9, wherein the first encoder has a number of bars equal to 1.