CA2071520C - Elimination of activated lymphocytes - Google Patents
Elimination of activated lymphocytes Download PDFInfo
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- CA2071520C CA2071520C CA002071520A CA2071520A CA2071520C CA 2071520 C CA2071520 C CA 2071520C CA 002071520 A CA002071520 A CA 002071520A CA 2071520 A CA2071520 A CA 2071520A CA 2071520 C CA2071520 C CA 2071520C
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- lymphocytes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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Abstract
2-Methyl-1-octadecylglycero-(3)-phosphocholine is suitable for killing mammalian lymphocytes activated by antigens or mitogens.
Description
D a s c r i p t i o n The T and 8 lymphocytes are essential components of the immune system in mammals. During their development they form specific receptors for antigens so that each such lymphocyte acquires specificity for a single antigen for the rest of its life-span. The resting lymphocytes (small lymphocytes) including the memory cells circulate through the body tissues and lymph organs as well as through the body fluids and thus monitor the body for the appearance of their antigens. If the specific antigen appears, an antigen-induced lymphocyte proliferation occurs with formation of the activated large lymphocytes. This proliferation can also be demonstrated in vitro by culturing the lymphoid cells with special antigens. Using the same system it can also be shown that mitogenic lectins, that is proteins which bind and cross-link specific cell surface determinants which are composed of carbohydrates, also stimulate lymphoid cells. Lymphocyte activation by either antigens or mitogens finally leads to the maturation of the lymphocyte to form a lymphoblast. The mitogenic stimulation of lymphocytes can for example be triggered experimentally by phytohaemagglutinin (PHA) and concanavalin A (Con A) in the case of T cells of human and animal origin and by lipopolysaccharides (LPS) in the case of B cells.
The primary immune response is therefore the result of stimulation of those lymphocytes which are specific for the antigen or mitogen so that these are transformed from the resting state into the activated state and become large lymphocytes which proliferate and differentiate to form effector cells (for example T
cells with cytotoxic or other functions or antibody-forming plasma cells which are formed from mature B
cells) or memory cells. The secondary immune response is then triggered by activation of the resting memory cells which in turn produces effector cells and memory cells.
The primary or secondary immune response then causes desired as well as undesired consecutive symptoms. The consecutive symptoms, which are in most cases undesired, include for example rejection of transplants, allergic reactions and suchlike. In general they can be designated as acquired immunological diseases or symptoms caused by external antigens.
If it would be possible to selectively eliminate the activated lymphocytes without adversely changing the properties of the resting lymphocytes it would be possible by this means to prevent generally acquired immunological diseases which are caused by external antigens. In this way allergic reactions as well as transplant rejections could for example be prevented.
It is therefore the object of the present invention to provide an agent which is capable of specifically eliminating activated lymphocytes without impairing resting lymphocytes, in particular without adversely affecting resting lymphocytes with regard to their capability to be stimulated by antigens or mitogens.
This object is achieved by the use of 2-methyl-1-octadecylglycero-(3)-phosphocholine, denoted ET180CH3 in the following, for the elimination of antigen-activated or mitogen-activated lymphocytes in mammals or by the use of ET180CH3 for the production of a pharmaceutical 2~7~524 agent for the elimination of antigen-activated or mitogen-activated lymphocytes.
ET180CH3 and its production is known. Furthermore it is known that ET180CH3 can be used as an agent for tumours (DE-A1 2619686) and for multiple sclerosis (DE-A1 3530767). A specific elimination of activated lymphocytes as shown by the invention could not be deduced from this. The invention is based on the finding that ET180CH3 selectively eliminates lymphocytes activated by antigen or mitogen. Even a long exposure to ET180CH3 does not have a negative influence on the resting lymphocytes and enables them to be subsequently stimulated with antigens or mitogens. In particular it was found that even a long administration of ET180CH3 does not have any adverse effects on the immune reaction in vivo and this applies to the B cell as well as to the T cell reactions.
The new indication according to the present invention thus allows a selective elimination of activated large lymphocytes and thus prevents the immune reaction triggered by these lymphocytes. Since there is not a concurrent adverse effect on the resting lymphocytes, the effectiveness of the immune system per se is not impaired by the.agent according to the present invention: This represents a considerable advantage compared to previously known immunosuppresive agents which always have influenced the entire immune system and thus decisively weakened the defensive power of the organism to other antigens and mitogens. .
The effective dose of ET180CH3 depends on the type of administration. In general, when administered to humans doses of between 10 and 1000 mg/person/day are used for 20?1520 the oral administration. In this method of application which can for example be carried out by dissolving the active substance in a suitable vehicle such as milk, 30 to 300 mg/person/day are preferably used. If the administration is by infusion these doses can even be considerably increased. In the case of a local application it is possible to also use the usual concentrations of active substance.
The invention is elucidated by the following examples in conjunction with the figures. The figures show:
Fig. I A the incorporation of 3H-thymidine as a measure for the lymphocyte activity when cell activators are added.
Fig. I B the incorporation of 3H-thymidine by lymphocytes under the influence of cell activators with the addition of ET180CH3 on the first day Fig. I C a diagram similar to I B with the addition of ET180CH3 on the second day Fig. II A the incorporation of 3H-thymidine in stimulated lymphocytes Fig. II B a diagram similar to Fig. II A, however, with addition of ET180CH3, the cell stimulation occurring only after administration of 20?1.520 _,_ Fig. II C the control results without stimulation and addition of ET180CH3 Fig. III A shows the influence of ET180CH3 on the formation of cells producing specific antibodies Fig. III B shows the incorporation of thymidine by T
lymphocytes with and without pretreatment with ET180CH3 Fig. III C shows analogous results to Fig. 3B with B
lymphocytes Example 1 T lymphocytes were isolated from the spleen cells of Balb C mice by passage through nylon wool. These were subsequently activated in culture with the polyclonal T
cell activators Con A or anti-CD3 antibodies or as a control with the B cell activator LPS. In each case ET180CH3 (10 ~,g/ml) was added after one or two days to half the cultures. The other half served as a control.
On the third day of culture, 3H-thymidine was added to all cultures and its incorporation was measured on the fourth day.
Fig. I A shows the expected stimulation of the cells in the form of increased 3H-thymidine incorporation after polyclonal activation with Con A or anti-CD3 antibodies.
The slight increase after addition of the B cell mitogen LPS means that some remaining B lymphocytes were present in the cultures. All these results of activation were completely suppressed by the addition of ET180CH3 to the cultures on the first day (see Fig. 1B) and almost as completely by addition on the second day (Fig. 1C).
Hence it follows that ET180CH3 almost completely prevents the proliferation of T and B lymphocytes of the mouse in vitro. The activators used cause the first cell division after about 24 hours so that when ET180CH3 is added at this time it can also prevent the cells entering the first S phase. Since, however, the addition of ET180CH3 after 48 hours still causes an almost complete inhibition this proves that cells which are already proliferating are also highly sensitive to ET180CH3.
20?1520 Example 2 The following experiments were carried out to determine whether ET180CH3 can be used in suitable concentrations to specifically eliminate only the activated and proliferating cells from a population of lymphocytes while sparing the resting lymphocytes:
T lymphocytes from Balb C mice (H-2d) purified by nylon wool were co-cultured with spleen cells of C57B16 mice (H-2b) along the lines of a "mixed lymphocyte reaction".
ET180CH3 (10 ~,g/ml) was added to one half of the cultures on the third day, the other half served as a control. A further control culture was composed of Balb C T lymphocytes alone and without ET180CH3. After 7 days culture, all cells were washed to remove ET180CH3 and again stimulated in culture with cells of C57B16 mice or with cells of CBA mice (H-2K), with the polyclonal T cell activators Con A or anti-CD3 antibodies or with the B cell mitogen LPS. 3H-thymidine was then added after three days and its incorporation was determined after a further day.
Fig. II A shows the results for the controls without ETI8oCH3. It should be noted in this case that the cultures without further additions also already showed a relatively high background incorporation of thymidine which masks a further increase after stimulation. In this case the only one which gave a significant increase in incorporation was Con A.
The results of the culture with ET180CH3 addition are shown in Fig. II B. The unspecific background value has completely disappeared in this case since unspecifically -lo-proliferating cells had been eliminated. Even the cultures restimulated with C57B16 cells did not show any further 3H-thymidine incorporation. However, the reaction to the new allogenic stimulation with CBA cells and in particular the very good reaction to Con A and anti-CD3 antibodies is remarkable. LPS did not result in a stimulation since the B lymphocytes had died during the course of the culture.
Fig. II C shows the results for the totally unstimulated controls and without ET180CH3. The lack of significant effects of stimulation even with Con A can be explained by the fact that unstimulated mouse lymphocytes only poorly survive a 9-day culture period.
These results show that those T lymphocytes which had been specifically activated to proliferate by an allo-antigen, in this case H-2b of C57B16 mice, were completely eliminated in the presence of ET-18. However, in contrast, T lymphocytes with other antigen specificities which thus persisted in the resting state, were not only preserved but were even subsequently very capable of being activated to proliferate. This was proven by the reaction to CBA, Con A and anti-CD3 antibodies. The fact that completely unstimulated lymphocytes (Fig. II C) were not capable of being stimulated even without ET180CH3 shows that ET180CH3 does not damage resting cells in any way.
Thus this experiment shows that antigen-specific, activated T cell clones can be selectively eliminated by means of ET180CH3, however, that T cells of other antigen specificities are not affected by this and remain thoroughly reactive.
20'1520 Example 3 C57B16 mice were each immunized with 100 ~.g of the classical carrier-hapten-antigen TNP-KLH (trinitrophenyl keyhole limpet haemocyanin). After 8 weeks the animals received a booster injection of 30 fag TNP-KLH each.
Concurrently with this and then daily for a total of 5 days some of the animals received 1 mg ETI8oCH3 in milk per animal per day by means of an oesophageal tube the other animals received milk without ET180CH3. One week after the boost or after the first dose of ETI8oCH3, the spleens of the animals were removed. The spleens of non-immunized animals with and without ET180CH3 served as a control.
A portion of the spleen cells was used to carry out direct and indirect haemolytic plaque tests for the detection of B lymphocytes which produce anti-TNP-specific antibodies of the IgM or IgG class.
Fig. III A shows that the formation of cells producing specific antibodies is not influenced by ET180CH3 in vivo. The specificity of the data is demonstrated by the small number of cells producing antibodies in the non-immunized animals that corresponds to background values.
This result shows that ET180CH3 does not exert any inhibitory effect in vivo on the primary or secondary humoral immune reaction as measured by the formation of B lymphocytes which produce specific antibodies after addition of antigens.
A further portion of the aforementioned spleen cells was cultured in vitro and KLH (restimulation of T
- 1z - 207120 lymphocytes), concanavalin A (general T cell mitogen), TNP-KLH (restimulation of B lymphocytes) or SRBC (sheep erythrocytes for the primary stimulation of B
lymphocytes in vitro) was added.
The T cell reactions were determined in the proliferation test by incorporation of 3H-thymidine, the B cell reactions were determined in the haemolytic plaque test.
Fig. III B shows the incorporation of thymidine by T
lymphocytes restimulated by KLH and activated by Con A
from animals without ET180CH3 pretreatment, on the left, and with Et180CH3 pretreatment, on the right. This shows that the restimulation with KLH is dose-dependent and is specific. The in vivo pretreatment of the animals with ET180CH3 does not have any adverse effect on the T cell restimulation or on mitogenic stimulation.
Fig. III C shows the results for B lymphocytes. The restimulation with TNP-KLH is specific, as is the primary stimulation with SRBC. Also in this case the cells from animals pretreated with ET180CH3 react at least as well as those from control animals. Resting T
cells as well as resting B cells thus preserve their capability of being stimulated even after administration of ET180CH3.
The primary immune response is therefore the result of stimulation of those lymphocytes which are specific for the antigen or mitogen so that these are transformed from the resting state into the activated state and become large lymphocytes which proliferate and differentiate to form effector cells (for example T
cells with cytotoxic or other functions or antibody-forming plasma cells which are formed from mature B
cells) or memory cells. The secondary immune response is then triggered by activation of the resting memory cells which in turn produces effector cells and memory cells.
The primary or secondary immune response then causes desired as well as undesired consecutive symptoms. The consecutive symptoms, which are in most cases undesired, include for example rejection of transplants, allergic reactions and suchlike. In general they can be designated as acquired immunological diseases or symptoms caused by external antigens.
If it would be possible to selectively eliminate the activated lymphocytes without adversely changing the properties of the resting lymphocytes it would be possible by this means to prevent generally acquired immunological diseases which are caused by external antigens. In this way allergic reactions as well as transplant rejections could for example be prevented.
It is therefore the object of the present invention to provide an agent which is capable of specifically eliminating activated lymphocytes without impairing resting lymphocytes, in particular without adversely affecting resting lymphocytes with regard to their capability to be stimulated by antigens or mitogens.
This object is achieved by the use of 2-methyl-1-octadecylglycero-(3)-phosphocholine, denoted ET180CH3 in the following, for the elimination of antigen-activated or mitogen-activated lymphocytes in mammals or by the use of ET180CH3 for the production of a pharmaceutical 2~7~524 agent for the elimination of antigen-activated or mitogen-activated lymphocytes.
ET180CH3 and its production is known. Furthermore it is known that ET180CH3 can be used as an agent for tumours (DE-A1 2619686) and for multiple sclerosis (DE-A1 3530767). A specific elimination of activated lymphocytes as shown by the invention could not be deduced from this. The invention is based on the finding that ET180CH3 selectively eliminates lymphocytes activated by antigen or mitogen. Even a long exposure to ET180CH3 does not have a negative influence on the resting lymphocytes and enables them to be subsequently stimulated with antigens or mitogens. In particular it was found that even a long administration of ET180CH3 does not have any adverse effects on the immune reaction in vivo and this applies to the B cell as well as to the T cell reactions.
The new indication according to the present invention thus allows a selective elimination of activated large lymphocytes and thus prevents the immune reaction triggered by these lymphocytes. Since there is not a concurrent adverse effect on the resting lymphocytes, the effectiveness of the immune system per se is not impaired by the.agent according to the present invention: This represents a considerable advantage compared to previously known immunosuppresive agents which always have influenced the entire immune system and thus decisively weakened the defensive power of the organism to other antigens and mitogens. .
The effective dose of ET180CH3 depends on the type of administration. In general, when administered to humans doses of between 10 and 1000 mg/person/day are used for 20?1520 the oral administration. In this method of application which can for example be carried out by dissolving the active substance in a suitable vehicle such as milk, 30 to 300 mg/person/day are preferably used. If the administration is by infusion these doses can even be considerably increased. In the case of a local application it is possible to also use the usual concentrations of active substance.
The invention is elucidated by the following examples in conjunction with the figures. The figures show:
Fig. I A the incorporation of 3H-thymidine as a measure for the lymphocyte activity when cell activators are added.
Fig. I B the incorporation of 3H-thymidine by lymphocytes under the influence of cell activators with the addition of ET180CH3 on the first day Fig. I C a diagram similar to I B with the addition of ET180CH3 on the second day Fig. II A the incorporation of 3H-thymidine in stimulated lymphocytes Fig. II B a diagram similar to Fig. II A, however, with addition of ET180CH3, the cell stimulation occurring only after administration of 20?1.520 _,_ Fig. II C the control results without stimulation and addition of ET180CH3 Fig. III A shows the influence of ET180CH3 on the formation of cells producing specific antibodies Fig. III B shows the incorporation of thymidine by T
lymphocytes with and without pretreatment with ET180CH3 Fig. III C shows analogous results to Fig. 3B with B
lymphocytes Example 1 T lymphocytes were isolated from the spleen cells of Balb C mice by passage through nylon wool. These were subsequently activated in culture with the polyclonal T
cell activators Con A or anti-CD3 antibodies or as a control with the B cell activator LPS. In each case ET180CH3 (10 ~,g/ml) was added after one or two days to half the cultures. The other half served as a control.
On the third day of culture, 3H-thymidine was added to all cultures and its incorporation was measured on the fourth day.
Fig. I A shows the expected stimulation of the cells in the form of increased 3H-thymidine incorporation after polyclonal activation with Con A or anti-CD3 antibodies.
The slight increase after addition of the B cell mitogen LPS means that some remaining B lymphocytes were present in the cultures. All these results of activation were completely suppressed by the addition of ET180CH3 to the cultures on the first day (see Fig. 1B) and almost as completely by addition on the second day (Fig. 1C).
Hence it follows that ET180CH3 almost completely prevents the proliferation of T and B lymphocytes of the mouse in vitro. The activators used cause the first cell division after about 24 hours so that when ET180CH3 is added at this time it can also prevent the cells entering the first S phase. Since, however, the addition of ET180CH3 after 48 hours still causes an almost complete inhibition this proves that cells which are already proliferating are also highly sensitive to ET180CH3.
20?1520 Example 2 The following experiments were carried out to determine whether ET180CH3 can be used in suitable concentrations to specifically eliminate only the activated and proliferating cells from a population of lymphocytes while sparing the resting lymphocytes:
T lymphocytes from Balb C mice (H-2d) purified by nylon wool were co-cultured with spleen cells of C57B16 mice (H-2b) along the lines of a "mixed lymphocyte reaction".
ET180CH3 (10 ~,g/ml) was added to one half of the cultures on the third day, the other half served as a control. A further control culture was composed of Balb C T lymphocytes alone and without ET180CH3. After 7 days culture, all cells were washed to remove ET180CH3 and again stimulated in culture with cells of C57B16 mice or with cells of CBA mice (H-2K), with the polyclonal T cell activators Con A or anti-CD3 antibodies or with the B cell mitogen LPS. 3H-thymidine was then added after three days and its incorporation was determined after a further day.
Fig. II A shows the results for the controls without ETI8oCH3. It should be noted in this case that the cultures without further additions also already showed a relatively high background incorporation of thymidine which masks a further increase after stimulation. In this case the only one which gave a significant increase in incorporation was Con A.
The results of the culture with ET180CH3 addition are shown in Fig. II B. The unspecific background value has completely disappeared in this case since unspecifically -lo-proliferating cells had been eliminated. Even the cultures restimulated with C57B16 cells did not show any further 3H-thymidine incorporation. However, the reaction to the new allogenic stimulation with CBA cells and in particular the very good reaction to Con A and anti-CD3 antibodies is remarkable. LPS did not result in a stimulation since the B lymphocytes had died during the course of the culture.
Fig. II C shows the results for the totally unstimulated controls and without ET180CH3. The lack of significant effects of stimulation even with Con A can be explained by the fact that unstimulated mouse lymphocytes only poorly survive a 9-day culture period.
These results show that those T lymphocytes which had been specifically activated to proliferate by an allo-antigen, in this case H-2b of C57B16 mice, were completely eliminated in the presence of ET-18. However, in contrast, T lymphocytes with other antigen specificities which thus persisted in the resting state, were not only preserved but were even subsequently very capable of being activated to proliferate. This was proven by the reaction to CBA, Con A and anti-CD3 antibodies. The fact that completely unstimulated lymphocytes (Fig. II C) were not capable of being stimulated even without ET180CH3 shows that ET180CH3 does not damage resting cells in any way.
Thus this experiment shows that antigen-specific, activated T cell clones can be selectively eliminated by means of ET180CH3, however, that T cells of other antigen specificities are not affected by this and remain thoroughly reactive.
20'1520 Example 3 C57B16 mice were each immunized with 100 ~.g of the classical carrier-hapten-antigen TNP-KLH (trinitrophenyl keyhole limpet haemocyanin). After 8 weeks the animals received a booster injection of 30 fag TNP-KLH each.
Concurrently with this and then daily for a total of 5 days some of the animals received 1 mg ETI8oCH3 in milk per animal per day by means of an oesophageal tube the other animals received milk without ET180CH3. One week after the boost or after the first dose of ETI8oCH3, the spleens of the animals were removed. The spleens of non-immunized animals with and without ET180CH3 served as a control.
A portion of the spleen cells was used to carry out direct and indirect haemolytic plaque tests for the detection of B lymphocytes which produce anti-TNP-specific antibodies of the IgM or IgG class.
Fig. III A shows that the formation of cells producing specific antibodies is not influenced by ET180CH3 in vivo. The specificity of the data is demonstrated by the small number of cells producing antibodies in the non-immunized animals that corresponds to background values.
This result shows that ET180CH3 does not exert any inhibitory effect in vivo on the primary or secondary humoral immune reaction as measured by the formation of B lymphocytes which produce specific antibodies after addition of antigens.
A further portion of the aforementioned spleen cells was cultured in vitro and KLH (restimulation of T
- 1z - 207120 lymphocytes), concanavalin A (general T cell mitogen), TNP-KLH (restimulation of B lymphocytes) or SRBC (sheep erythrocytes for the primary stimulation of B
lymphocytes in vitro) was added.
The T cell reactions were determined in the proliferation test by incorporation of 3H-thymidine, the B cell reactions were determined in the haemolytic plaque test.
Fig. III B shows the incorporation of thymidine by T
lymphocytes restimulated by KLH and activated by Con A
from animals without ET180CH3 pretreatment, on the left, and with Et180CH3 pretreatment, on the right. This shows that the restimulation with KLH is dose-dependent and is specific. The in vivo pretreatment of the animals with ET180CH3 does not have any adverse effect on the T cell restimulation or on mitogenic stimulation.
Fig. III C shows the results for B lymphocytes. The restimulation with TNP-KLH is specific, as is the primary stimulation with SRBC. Also in this case the cells from animals pretreated with ET180CH3 react at least as well as those from control animals. Resting T
cells as well as resting B cells thus preserve their capability of being stimulated even after administration of ET180CH3.
Claims (6)
1. 2-Methyl-1-octadecylglycero-(3)-phosphocholine for use in the complete suppression of the formation of antigen-activated or mitogen-activated T and B
lymphocytes in mammals.
lymphocytes in mammals.
2. Use of 2-methyl-1-octadecylglycero-(3)-phosphocholine for the production of a pharma-ceutical agent for the complete suppression of the formation of antigen-activated or mitogen-activated T and B
lymphocytes.
lymphocytes.
3. Use of 2-methyl-1-octadecylglycero-(3)-phos-phocholine as an anti-acquired immunological disease agent, for the complete suppression of the formation of antigen-activated or mitogen-activated T and B
lymphocytes.
lymphocytes.
4. An antigen-activated or mitogen activated T and B lymphocytes suppressive pharmaceutical composition comprising an acceptable, effective amount of 2-methyl-1-octadecylglycero-(3)-phosphocholine, for complete suppression of formation of antigen-activated or mitogen-activated T and B lymphocytes, in association with a pharmaceutically acceptable carrier.
5. An anti-acquired immunological disease pharmaceutical composition comprising an acceptable, effective amount of 2-methyl-1-octadecylglycero-(3)-phosphocholine as an anti-acquired immunological disease agent for complete suppression of formation of antigen-activated or mitogen-activated T and B lymphocytes, in association with a pharmaceutically acceptable carrier.
6. An anti-transplant rejection pharmaceutical composition comprising an acceptable, effective amount of 2-methyl-1-octadecylglycero-(3)-phosphocholine, for complete suppression of formation of antigen-activated or mitogen-activated T and B lymphocytes, in association with a pharmaceutically acceptable carrier.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3941009A DE3941009A1 (en) | 1989-12-12 | 1989-12-12 | ELIMINATION OF ACTIVATED LYMPHOCYTES |
| DEP3941009.9 | 1989-12-12 | ||
| PCT/EP1990/002233 WO1991008746A1 (en) | 1989-12-12 | 1990-12-11 | Killing of activated lymphocytes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2071520A1 CA2071520A1 (en) | 1991-06-13 |
| CA2071520C true CA2071520C (en) | 2002-10-01 |
Family
ID=6395316
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002071520A Expired - Fee Related CA2071520C (en) | 1989-12-12 | 1990-12-11 | Elimination of activated lymphocytes |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0505414B1 (en) |
| JP (1) | JPH05504132A (en) |
| AT (1) | ATE102038T1 (en) |
| AU (1) | AU638086B2 (en) |
| CA (1) | CA2071520C (en) |
| DE (2) | DE3941009A1 (en) |
| DK (1) | DK0505414T3 (en) |
| ES (1) | ES2062754T3 (en) |
| FI (1) | FI922710A0 (en) |
| HU (1) | HU217586B (en) |
| NO (1) | NO922304L (en) |
| RU (1) | RU2100025C1 (en) |
| WO (1) | WO1991008746A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5517234A (en) * | 1993-10-26 | 1996-05-14 | Gerber Systems Corporation | Automatic optical inspection system having a weighted transition database |
| DE19822509A1 (en) * | 1998-05-19 | 1999-11-25 | Medmark Pharma Gmbh | Use of edelfosin for treatment of brain tumors, especially by oral administration |
| DE19829448A1 (en) * | 1998-07-01 | 2000-10-12 | Medmark Pharma Gmbh | 1-Octadecyl-2-methyl-sn-glycero-3-phosphocholine (ET180CH3) for the treatment of human breast cancer |
| AU2006328957C1 (en) | 2005-12-23 | 2013-01-10 | Jado Technologies Gmbh | Means and methods for the treatment and prevention of allergic diseases |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3918082A1 (en) * | 1989-06-02 | 1991-01-24 | Max Planck Gesellschaft | AGENT FOR AUTOIMMUNE DISEASES |
-
1989
- 1989-12-12 DE DE3941009A patent/DE3941009A1/en not_active Withdrawn
-
1990
- 1990-12-11 RU SU925052304A patent/RU2100025C1/en active
- 1990-12-11 HU HU9201976A patent/HU217586B/en not_active IP Right Cessation
- 1990-12-11 CA CA002071520A patent/CA2071520C/en not_active Expired - Fee Related
- 1990-12-11 EP EP91900757A patent/EP0505414B1/en not_active Expired - Lifetime
- 1990-12-11 ES ES91900757T patent/ES2062754T3/en not_active Expired - Lifetime
- 1990-12-11 DK DK91900757.5T patent/DK0505414T3/en active
- 1990-12-11 AT AT91900757T patent/ATE102038T1/en not_active IP Right Cessation
- 1990-12-11 AU AU69543/91A patent/AU638086B2/en not_active Ceased
- 1990-12-11 JP JP3501246A patent/JPH05504132A/en active Pending
- 1990-12-11 WO PCT/EP1990/002233 patent/WO1991008746A1/en active IP Right Grant
- 1990-12-11 DE DE91900757T patent/DE59004836D1/en not_active Expired - Fee Related
-
1992
- 1992-06-11 FI FI922710A patent/FI922710A0/en not_active Application Discontinuation
- 1992-06-11 NO NO92922304A patent/NO922304L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI922710A0 (en) | 1992-06-11 |
| DE59004836D1 (en) | 1994-04-07 |
| ES2062754T3 (en) | 1994-12-16 |
| AU638086B2 (en) | 1993-06-17 |
| AU6954391A (en) | 1991-07-18 |
| CA2071520A1 (en) | 1991-06-13 |
| HU9201976D0 (en) | 1992-09-28 |
| RU2100025C1 (en) | 1997-12-27 |
| WO1991008746A1 (en) | 1991-06-27 |
| DK0505414T3 (en) | 1994-05-09 |
| JPH05504132A (en) | 1993-07-01 |
| ATE102038T1 (en) | 1994-03-15 |
| DE3941009A1 (en) | 1991-06-13 |
| EP0505414B1 (en) | 1994-03-02 |
| NO922304D0 (en) | 1992-06-11 |
| EP0505414A1 (en) | 1992-09-30 |
| NO922304L (en) | 1992-06-11 |
| HUT60927A (en) | 1992-11-30 |
| HU217586B (en) | 2000-02-28 |
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