Process for therapeutic dissociation of immune complexes and removal of antigens

• US 4,663,049 A
• Filed: 07/05/1984
• Issued: 05/05/1987
• Est. Priority Date: 07/05/1984
• Status: Expired due to Fees

• Current Assignee: University of Utah (State of Utah)
• Original Assignee: University of Utah (State of Utah)
• Inventors: Kolff, Willem J., Shettigar, Udipi R.
• Primary Examiner(s): SPEAR JR, FRANK
• Application Number:
  US06/627,961
• Time in Patent Office: 1,034 Days
• Field of Search: 604/4, 604/5, 604/6, 210/645, 210/651, 210/641, 210/433.2
• US Class Current: 210/641
• CPC Class Codes: A61K 35/16 Blood plasma; Blood serum umbilical cord blood A61K35/51
• CPC Class Codes: A61M 1/3472 with treatment of the filtrate
• CPC Class Codes: A61M 1/3479 by dialysing the filtrate
• CPC Class Codes: A61M 1/3482 by filtrating the filtrate using another cross-flow filter, e.g. a membrane filter
• CPC Class Codes: A61M 1/3486 Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
• CPC Class Codes: A61M 1/3623 Means for actively controlling temperature of blood

Abstract

The present invention provides an improved method for treating blood to remove foreign substances such as immune complexes and free antigen. This is advantageously accomplished by separating a portion of a patient'"'"'s blood as plasma, and acidifying the plasma to a pH below about 3.1 in order to cause the immune complexes to dissociate into antigen and antibody. After removing the antigen, the plasma is returned to the patient. Preferably, the patient'"'"'s blood is substantially diluted prior to plasma separation, thereby substantially increasing the clearance rate of the plasma separator device and also washing off antigens bound to cellular blood components. Also, it is preferred that the plasma fraction is further diluted during the acidification step. Subsequent removal of excess fluid will cause substantial removal of free antigen. In a presently preferred process, the excess fluid volume is reduced by use of an ultrafiltration device capable of passing antigen, but not larger protein constituents of plasma. The resultant plasma solution is advantageously subjected to dialysis to simultaneously remove remaining antigen and to raise the pH back to a physiological level.

Claims

1. A method for removing antigens from a patient'"'"'s circulatory system, comprising the steps of:

obtaining blood containing antigens from a patient;

diluting the blood by adding a physiologically compatible electrolyte solution containing low molecular weight constituents of plasma so as to wash off at least a portion of the antigens from cellular components present in the blood prior to plasma separation;

separating a plasma fraction from the cellular components of the diluted blood, said separated plasma containing antigens;

removing the antigens from the plasma;

removing excess plasma fluid without removing substantial amounts of plasma protein so as to reduce the volume of plasma;

mixing the reduceed volume of plasma with the cellular blood components; and

returning the treated blood to the patient.

2. A method for removing antigens from a patient'"'"'s circulatory system as defined in claim 1, where from about 40 percent to about 60 percent of the diluted blood is separated as a plasma fraction.

3. A method for removing antigens from a patient'"'"'s circulatory system as defined in claim 1 comprising the further step of adding a substantial amount of a dilution fluid to the separated plasma prior to removing the antigens so as to substantially dilute the concentration of antigens per unit of plasma, and wherein the step of removing excess plasma fluid is conducted in a manner such that a portion of the antigens are removed with said excess plasma fluid.

4. A method for removing antigens from a patient'"'"'s circulatory system as defined in claim 1, wherein the excess plasma fluid is removed by passing the plasma fraction through ultrafiltration means capable of passing the antigens together with plasma fluid into the filtrate, but not capable of passing plasma proteins.

5. A method for removing antigens from a patient'"'"'s circulatory system as defined in claim 4, wherein the plasma passing through the ultrafiltration means is passed through dialysis means to remove additional antigens.

6. A method for removing antigens from a patient'"'"'s circulatory system as defined in claim 3, wherein the excess plasma fluid is removed by passing the plasma fraction through ultrafiltration means capable of passing the antigens together with plasma fluid into the filtrate, but not capable of passing plasma proteins.

7. A method for removing antigens from a patient'"'"'s circulatory system as defined in claim 6, wherein the plasma passing through the ultrafiltration means is passed through dialysis means to remove additional antigens.

8. A method for removing antigens from a patient'"'"'s circulatory system as defined in claim 1, wherein the antigens are tumor antigens.

9. A method for removing antigens from a patient'"'"'s circulatory system as defined in claim 1, wherein the antigens are a drug.

10. A method for removing antigens from a patient'"'"'s circulatory system as defined in claim 1, wherein the antigens are toxins.

11. A method for removing circulating antigens from a patient'"'"'s circulatory system, comprising the steps of:

obtaining from a patient blood containing immune complexes;

separating a portion of the plasma component of the blood from the cellular components of the blood, said separated plasma containing immune complexes;

mixing a sufficient volume of an acid to the separated plasma in order to reduce the pH of the plasma to a pH such that the immune complexes in the plasma will dissociate into respective antigens and antibodies;

removing the antigens from the plasma;

mixing the treated plasma with the cellular blood components; and

returning the treated blood and antibodies contained therein to the patient.

12. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 11, wherein the step of adding acid to the separated plasma comprises lowering the pH of the plasma to a pH of about 3.1.

13. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 12, wherein the acid used is dilute hydrochloric acid.

14. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 11, wherein a substantial amount of acid solution is added to the separated plasma so as to substantially dilute the concentration of antigens per unit of plasma, and further comprising the step of removing excess plasma fluid in a manner such that a portion of the antigens are removed with said excess plasma fluid.

15. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 14, wherein a sufficient amount of acid solution is added such that the concentration of antigens per unit of plasma is diluted to within the range of about 30 percent to about 70 percent of the concentration of antigens in the plasma prior to dilution.

16. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 11, comprising the further step of adding a substantial amount of a dilution fluid to the patient'"'"'s blood prior to separating a portion of the blood as plasma so that an increased percentage of the blood volume is separated as plasma during the plasma separation step.

17. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 11, comprising the further step of adding a substantial amount of a dilution fluid to the patient'"'"'s blood prior to separating a portion of the blood as plasma so that a significant number of antigens bound to cellular blood components will become detached from such cellular blood components.

18. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 16, wherein a sufficient amount of dilution fluid is added to the blood so as to dilute the concentration of immune complexes per unit of blood to within the range of about 30 percent to about 70 percent of the concentration of immune complexes the blood prior to dilution.

19. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 18, wherein about 40 percent to about 70 percent of the total volume of diluted blood is separated as plasma.

20. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 16, wherein the dilution fluid is a physiologically compatible electrolyte solution containing low molecular weight constituents of normal plasma.

21. A method for removing circulating antigens from a patient'"'"'s circulatory system, comprising the steps of:

obtaining from a patient blood containing immune complexes;

separating a portion of the plasma component of the blood from the cellular components of the blood, said separated plasma containing immune complexes;

mixing a sufficient volume of a weak acid to the separated plasma in order to substantially dilute the concentration of immune complexes per unit of plasma and to reduce the pH of the diluted plasma sufficiently so that the immune complexes in the plasma will dissociate into respective antigens and antibodies;

removing the antigens from the plasma;

removing excess plasma fluid without removing substantial amounts of plasma protein so as to reduce the volume of plasma;

adding a basic material to the reduced volume of plasma so as to raise the pH of the reduced volume of plasma to a physiological pH;

mixing the reduced volume of plasma with the cellular blood components; and

returning the treated blood and antibodies contained therein to the patient.

22. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 21, wherein the weak acid comprises a solution containing hydrochloric acid.

23. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 21, wherein the pH of the separated plasma is reduced to about 3.1 in order to dissociate the immune complexes.

24. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 21, wherein a sufficient amount of acid solution is added to dilute the separated plasma by about 30 percent to about 70 percent.

25. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 24, wherein excess plasma fluid is removed following addition of the acid solution by passing the diluted plasma through ultrafiltration means capable of passing antigens together with fluid into the filtrate, but not capable of passing plasma proteins having a higher molecular weight.

26. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 25, wherein the plasma passing through the ultrafiltration means is passed through dialysis means to remove additional antigens.

27. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 26, wherein the dialysis means also serves to raise the pH of the plasma to a physiological level.

28. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 21, comprising the further step of adding a substantial amount of a dilution fluid to the patient'"'"'s blood prior to separating a portion of the blood as plasma so that an increased percentage of the blood volume is separated as plasma during the plasma separation step.

29. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 21, comprising the further step of adding a substantial amount of a dilution fluid to the patient'"'"'s blood prior to separating a portion of the blood as plasma so that a significant number of antigens bound to cellular blood components will become detached from such cellular blood components.

30. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 28, wherein a sufficient amount of dilution fluid is added to the blood so as to dilute the concentration of immune complexes per unit of blood to within the range of about 30 percent to about 70 percent of the concentration of immune complexes in the blood prior to dilution.

31. A method for removing circulating antigens from a patient'"'"'s circulatory system as defined in claim 28 wherein the dilution fluid is a physiologically compatible electrolyte solution containing low molecular weight constituents of normal plasma.

32. A method for removing circulating antigens from a patient'"'"'s circulatory system, comprising the steps of:

obtaining from a patient blood containing immune complexes;

diluting the blood prior to plasma separation by adding a dilution fluid containing low molecular weight constituents of plasma;

separating from about 40 percent to about 60 percent of the diluted blood as a plasma fraction from the cellular components of the blood, said separated plasma containing immune complexes;

diluting the plasma fraction by addition of an acid solution in order to substantially dilute the concentration of immune complexes per unit of plasma and also to reduce the pH of the diluted plasma sufficiently so that the immune complexes in the diluted plasma will dissociate into respective antigens and antibodies;

removing excess plasma fluid without removing substantial amounts of plasma protein so as to reduce the volume of plasma and to simultaneously remove antigens;

removing additional antigens from the reduced volume of plasma;

adding a basic material to the reduced volume of plasma to raise the pH of thee reduced volume of plasma to a physilological pH;

mixing the reduced volume of plasma with the cellular blood components; and

returning the treated blood to the patient.