TREATMENT APPARATUS AND METHOD FOR EXTRACORPOREAL IMMUNOTOLERANCE ENHANCING BLOOD TREATMENT

Abstract

The invention relates to a treatment device (100) which is designed for extracorporeal blood treatment of blood of a subject (2) for an immunotolerance enhancement of the subject (2), comprising at least one container (10) which has an interior (11) for receiving a blood sample (1) of blood of the subject (2) and an exchange device (20) designed to supply and/or discharge the blood sample (1) into or out of the interior (11) of the container (10) and comprising a cell exposure device (30) which is positioned in the container (10) and has biological cell material (31) with surface molecules, said cell material being arranged in the interior (11) of the container (10) for a material interaction with the blood sample (1), including a reaction of endogenous immune cells in the blood with the surface molecules of the cell material. The invention also relates to a kit for extracorporeal blood treatment and to a method for operating the treatment device.

Claims

1. A treatment apparatus, which is designed for extracorporeal blood treatment of blood from a subject for an immunotolerance enhancement of the subject, comprising: at least one container which has an interior for receiving a blood sample of blood from the subject and an exchange device which is designed to supply and/or discharge the blood sample into or out of an interior of the at least one container, and a cell exposure device which is positioned in the at least one container and has biological cell material with surface molecules, wherein the biological cell material is arranged in the interior of the at least one container for a material interaction with the blood sample, comprising a reaction of endogenous immune cells in the blood with the surface molecules of the biological cell material.

2. The treatment apparatus according to claim 1, wherein the cell exposure device has a separating layer, wherein the biological cell material is separated from the interior by the separating layer and the biological cell material is held on the cell exposure device and the separating layer is designed for a substance exchange between the biological cell material and the blood sample.

3. The treatment apparatus according to claim 1, wherein the cell exposure device has a support on which the biological cell material is arranged in an adherent state.

4. The treatment apparatus according to claim 3, wherein the support has a binding layer which is designed for an adherent binding of at least one of induced pluripotent stem cells (iPS cells), adult stem cells and cells differentiated therefrom.

5. The treatment apparatus according to claim 1, wherein the cell exposure device has a suspension space in which the biological cell material is arranged in at least one of a suspended state and/or on carrier beads.

6. The treatment apparatus according to claim 1, wherein the biological cell material comprises at least one of: exogenous biological cell material, endogenous biological cell material from the subject, at least one of cell-equivalent iPS cells and iPS cell constituents, at least one of organ-equivalent differentiated iPS cells and iPS cell components, organ-equivalent differentiated adult stem cells, at least one of biological cells and/o cell components which trigger immune responses in the blood, at least one of exogenous cells which are provided for allogeneic transplant into the subject, and components thereof, a composition of cell material which contains different cell types which carry characteristic HL antigens from a predetermined reference group of subjects, and cells which have been genetically modified to undergo cell death which can be stimulated at least one of externally and in a time-dependent manner.

7. The treatment apparatus according to claim 1, wherein the exchange device comprises at least one of the features: the exchange device has an inlet line and an outlet line which are in fluidic connection with the interior end are arranged mutually spaced apart, the exchange device is provided with a cannula which is designed for direct connection to the circulation of the subject, and the exchange device is provided with a pump which is arranged for blood transport into or out of the container.

8. The treatment apparatus according to claim 1, which comprises a retaining device which is arranged for retaining the biological cell material in the container.

9. The treatment apparatus according to claim 8, wherein the retaining device has a mechanically- or chemically-acting filter.

10. The treatment apparatus according to claim 8, wherein the retaining device is part of the exchange device.

11. The treatment apparatus according to claim 1, which comprises a convection device which is designed for moving the blood sample in the interior of the at least one container.

12. The treatment apparatus according to claim 11, wherein the convection device comprises at least one of a stirring mechanism in the interior and a tilting mechanism, to which the at least one container is coupled.

13. The treatment apparatus according to claim 11, wherein the at least one container has a flexible container wall and the convection device comprises a deformation device by way of which the at least one container is deformed.

14. The treatment apparatus according to claim 1, comprising a plurality of containers each with an exchange device and a cell exposure device, which has biological cell material, wherein the containers contain different types of biological material.

15. The treatment apparatus according to claim 1, which contains at least one of active substances which promote the development of immunotolerance, active substances which promote regulatory T cells, active substances which act on the mTOR system, at least one anticoagulant substance, and active substances which have at least one of an immunotolerance-enhancing action and a supporting function in inducing immunotolerance.

16. The treatment apparatus according to claim 1, which comprises at least one of a measuring device which is designed to detect substances from the blood sample which are bound to the biological cell material, and a collecting device which is designed to collect substances from the blood sample which are bound to the biological cell material.

17. A kit for extracorporeal blood treatment, comprising at least one treatment apparatus according to claim 1.

18. A method for operating a treatment apparatus according to claim 1 for extracorporeal blood treatment of blood from a subject for an immunotolerance enhancement of the subject, comprising the steps of: providing a blood sample to be treated of blood from the subject, introducing the blood sample into the at least one container of the treatment apparatus, treating the blood sample by an interaction, comprising a reaction of endogenous immune cells with the surface molecules of the presented biological cell material such that the blood sample after treatment is suitable for effecting an enhanced immunotolerance of the subject, and discharging the blood sample from the container.

19. The method according to claim 18, wherein the blood sample to be treated is at least one of provided in a supply reservoir and discharged into a collection reservoir.

20. The method according to claim 18, wherein the treatment apparatus is connected to the circulation of the subject, wherein the blood to be treated flows as the blood sample into the treatment apparatus and back out therefrom into the circulation.

21. The method according to claim 18, wherein the blood sample is moved during the treatment in the treatment apparatus.

22. The method according to claim 18, comprising the step of adjusting at least one of an amount and a concentration of the biological cell material in the treatment apparatus depending on a given or achieved immunotolerance of the subject.

23. The method according to claim 18, wherein the treatment apparatus is provided in a frozen state and is thawed before the blood sample is introduced into the container of the treatment apparatus.

24. The method according to claim 18, wherein a blood donation from the subject is at least one of provided in a supply reservoir and discharged into a collection reservoir.

25. The method according to claim 18, wherein the cell exposure device with the biological cell material is provided in a frozen state and is thawed before the blood sample is introduced into the at least one container of the treatment apparatus.

Description

[0048] Further details and advantages of the invention will be described below with reference to the appended drawings. The drawings show:

[0049] FIG. 1 a schematic overview of an embodiment of the treatment apparatus according to the invention;

[0050] FIGS. 2 to 4 features of further embodiments of the treatment apparatus according to the invention;

[0051] FIGS. 5 and 6 features of embodiments of the method according to the invention for extracorporeal blood treatment; and

[0052] FIG. 7 a schematic overview of features of further embodiments of the treatment apparatus according to the invention.

[0053] Embodiments of the invention are described below with reference to the structure of the treatment apparatus and the application thereof. Details of the preparation of the cell material, e.g. the production and optional differentiation of iPS cells or adult stems cells are not described, since they are known per se. By way of example, reference is made to a treatment apparatus having a cylindrical container and a cell exposure device adjacent to the interior on one side. The implementation of the invention is not restricted to this embodiment, but rather is possible correspondingly with other container shapes and differently configured cell exposure devices.

[0054] FIG. 1 schematically shows an embodiment of the treatment apparatus 100, comprising a cylindrical container 10, which has an interior 11 for receiving a blood sample 1 and an exchange device 20, a cell exposure device 30 with biological cell material 31 and a retaining device 40. The end faces of the interior 11 are closed with sterile sealing walls 12. The exchange device 20 comprises an inlet line 21 and an outlet line 22 (only a portion of each of which is shown, see also FIGS. 5 and 6), which are arranged on the opposite end faces of the interior 11 and lead through the sealing walls 12. The inlet line and the outlet line each contain a closable valve (not shown) for separating the interior 11 from the surroundings, e.g. during the treatment of the blood sample 1. The interior 11 has a volume of for example 100 ml.

[0055] The cell exposure device 30 comprises the biological cell material 31 which is arranged adherently bound to a solid support 32. The biological cell material 31 comprises, e.g. in the treatment of the blood sample 1 before a kidney transplantation, differentiated iPS cells which are produced from donor tissue and differentiated to give kidney tissue. In the example illustrated, the biological cell material 31 has a free surface such that the blood sample 1 in the interior 11 directly touches the biological cell material 31 (see enlargement B from FIG. 1, in FIG. 2).

[0056] The retaining device 40 comprises a filter which is attached to the outlet line 22 and retains chemically and/or mechanically unintentionally released parts of the cell material 31 in the treatment apparatus 100.

[0057] The container 10 forms a volume which is filled via at least one inlet, such as the inlet line 11, with the blood sample 1 from the subject (see arrow A). As illustrated, the container 10 can be shaped cylindrically, or else in some other shape, e.g. cuboid or prism-shaped. After the incubation of the blood sample 1 in the interior 11 and in the presence of the exogenous cell material, e.g. for a duration of 4 hours, the blood sample 1 is removed either via the abovementioned inlet or a second inlet, such as the outlet line 22. Alternatively to the depiction in FIG. 1, it is possible to directly connect the treatment apparatus 100 to a cannula and to transfer the blood directly via the cannula into the container and back again into the subject. This advantageously reduces the risk of contamination.

[0058] The biological cell material 31 is located in the container 10 on the support material 32, which cell material preferably has binding possibilities and presents these to the immune system components (e.g. T and B cells) in the blood sample 1. The exogenous cell material 31 can be mechanically stabilized (see FIG. 3) by a separating layer 33 lying over same, e.g. a membrane or frame structure. The support material 32 comprises polymers, biopolymers and/or hydrogels. Furthermore, anticoagulants can be introduced into the support material 32 and/or the interior 11, in order to reduce the risk of blood coagulation. Furthermore, active substances can be arranged in the support material 32 and/or in the interior 11, which promote the development of immunotolerance, e.g. the active substance rapamycin (see [2]).

[0059] Because the treatment apparatus 100 is intended to be used on site in medical institutions (doctor's surgeries, hospitals, laboratories), the container 10 as a whole can be frozen (e.g. below −130° C.) and stored. When the treatment apparatus 100 is then intended to be used, the thawing can take place for a specific period of time, or else the cells are directly thawed with the warm blood sample 1 from the subject. Alternatively, exclusively the support material 32 with the exogenous cell material 31 can be separately stored in a frozen state. In this case, the support material 32 with the exogenous cell material 31 is thawed shortly before use and transferred into the container 10, or is thawed directly in the container 10.

[0060] FIGS. 3 and 4 show alternative configurations of the cell exposure device 30 (corresponding to the section B from FIG. 1). In these embodiments, a separating layer 33 is provided, which separates the biological cell material 31 from the interior 11. Here, the biological cell material 31 can be securely attached to a support 32 (see FIG. 3) or arranged suspended in a suspension space 34 without support (see FIG. 4). The separating layer 33 is impermeable to the cells of the cell material 31 and the cell components thereof, such as cell membrane fragments, but permeable to antigen molecules. The separating layer 33 comprises e.g. polymers and/or hydrogels.

[0061] FIG. 5 illustrates a first method variant in which the treatment apparatus 100 is coupled more continuously with the circulation of the subject 2. Blood flows under the action of blood pressure, optionally aided by gravity and/or a pump (see FIG. 7), directly from the subject into the treatment apparatus 100 and from said treatment apparatus back to the subject 2. Here, a measuring device 60 can be provided in the outlet line, by means of which the immunotolerance achieved in the flowing blood is quantitatively detected. For example, antibodies (against major histocompatibility complexes) acting against the exogenous cell material can be measured in the subject's blood. For random sampling, e.g. an ELISpot measurement can be used. Depending on the measurement result, the blood can be returned to the treatment apparatus 100 again (see dashed arrow) in order to further enhance the immunotolerance.

[0062] Alternatively or in addition, the treatment apparatus 100, in particular the biological cell material therein, can also be used to evaluate the immune response. In this case, the adherent cells in the treatment apparatus 100 are analyzed after the blood reaction. To this end, the reduced viability of the adherent cells can be measured in an immune response. Furthermore, antibodies bound to the cells can be detected and quantified (e.g. by human antibodies directed against animal antibodies).

[0063] FIG. 6 illustrates a second method variant in which, in a first step (see FIG. 6A), the treatment apparatus 100 is loaded with a blood sample. The blood sample is, as in FIG. 5, taken directly from the subject or added to a supply reservoir (not shown) by a blood donation and transferred from the supply reservoir to the treatment apparatus 100. Subsequently, the blood sample is incubated (without connection to the subject 2) in the treatment apparatus 100 (see FIG. 6B). After the treatment of the blood sample, the blood is returned to the subject 2 (see FIG. 6C). In this case, too, a measurement to evaluate the immune response can be provided on the blood and/or cell material.

[0064] FIG. 7 shows further components of the treatment apparatus 100, which can be provided individually or in combination. The treatment apparatus 100 is as shown in FIG. 1. In addition, a pump 23 is provided, by means of which the blood flow through the container 10 is aided. Furthermore, a schematically depicted closable access opening 13, for example for measuring and/or monitoring purposes, can be provided in a container wall.

[0065] The schematically depicted convection device 50 comprises e.g. a tilting and/or deforming mechanism, by means of which the container 10 can be moved and/or deformed in order to move the blood sample 1 in the interior 11 of the container 10. Alternatively or in addition, a magnetic stirrer (not shown) can be provided in the interior.

[0066] FIG. 7 further schematically depicts the measuring device 60 which is designed to detect substances from the blood sample 1 which are bound to the biological cell material 31, in particular antibodies (see FIG. 5) and a collecting device 70 which is designed to collect substances from the blood sample 1 which are bound to the biological cell material 31, in particular antibodies, or non-binding components present in the blood.

[0067] The features of the invention disclosed in the above description, the drawings and the claims, whether individually or in combination or sub-combination, can be relevant to the implementation of the invention in its various configurations.