Preventing and treating chronic disorders using the modified vaccination technique

Arpad Zsigmond Barabas¹, Donald Mackay Weir², Chad Douglas Cole³, Arpad David Barabas¹, Nizar Jacques Bahlis⁴, Richard Milton Graeff⁵, Rene Lafreniere¹

1Department of Surgery, University of Calgary Health Sciences Centre, Calgary, Alberta, Canada, ²University of Edinburgh Medical School, Scotland,³Department of Neurosurgery, University of Utah, Salt Lake City, Utah, USA, ⁴Department of Medicine/Oncology, University of Calgary Health Sciences Centre, Calgary, Alberta, Canada, ⁵Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA

TABLE OF CONTENTS

1. Abstract

2. Introduction

3. Background to autoimmunity

4. The beneficial aspects of immune complexes in initiating and maintaining predetermined immune response outcomes

4.1. The biologics needed to make up the relevant immune complexes to combat human chronic disorders

4.1.1. To prevent or treat/terminate autoimmune diseases

4.1.2. To prevent or treat/terminate cancer

4.1.3. To prevent or treat/terminate presently incurable chronic diseases

5. Perspectives

6. Acknowledgement

7. References

1. ABSTRACT

It is anticipated that the ultimate solution for the prevention and termination of autoimmune disorders will be based on somehow manipulating the cells of the immune system to attain antigen (ag) specific downregulation and termination. In the last few years we have developed a new vaccination technique that we call "modified vaccination technique" (MVT). It has with equal effectiveness both prevented and terminated autoimmune disease causing events in an experimental autoimmune kidney disease model. We expect that our technique will be similarly applicable to the specific treatment and cure of numerous other chronic disorders presently treated only by drugs. The vaccine is composed of two components, an ag and a specific antibody against it. When these are combined at slight ag excess they constitute a vaccine which is capable of treating chronic ailments by redirecting immune response outcomes in the vaccinated host. Both components, like drugs, will have to be produced ex vivo in order to maintain uniformity, safety, efficacy, and specificity.

2. INTRODUCTION

The medications (i.e. drugs) presently used to treat patients for chronic ailments are nonspecific in their actions and can cause undesirable side effects. Even the monoclonal antibodies (abs) that have recently been produced for the treatment of certain disorders are nonspecific. Many, like Rituximab (1-4), control the progression of a disease by nonspecifically depressing the immunological cell lines that maintain the disease. The process affects not only those cells that contribute to the disease per se or to its progression, but also numerous other cell lines that are vitally important for normal immune system response against exogenous and endogenous antigens (ags).

Medication, monoclonal abs, and active and passive immunization programs have their roles to play in preventing, treating, and controlling numerous disorders. In the past few years, however, it has become evident that the prevention and cure of both endogenous source ag initiated and maintained disorders and chronic infections require a different approach (5-11). It is apparent from the medical literature that the solution for curing autoimmune disorders might very well lie in somehow influencing the immune system's cell lines by the appropriate presentation of the ag against which we want to upregulate (cancer, agents causing chronic infection) or downregulate (autoimmune diseases) an immune response.

We have developed a vaccination program, namely modified vaccination technique (MVT) (12,13). In a milder form of Heymann nephritis (HN) called slowly progressive Heymann nephritis (SPHN) (14), our MVT prevented the development of severe HN kidney lesions (12,15,16). When employed after the induction of SPHN, it terminated the pathogenic Immunoglobulin G (IgG) autoantibody (aab) mediated disease processes (15).

We have successfully employed the MVT in different situations (12,16,17) and found that it provided the desired immune response outcome in each case; namely downregulation or upregulation of immune events. This third method of vaccination (active and passive immunization being the other two) for the first time offers hope for the equally effective prevention and termination of endogenous source ag induced disorders and diseases caused by chronic infections.

3. BACKGROUND TO AUTOIMMUNITY

The key to preventing and curing chronic ailments (autoimmune diseases, cancer) is to determine the underlying immunological mechanisms responsible for the disease. The immune system is comprised partly of a complex autoimmune network that deals with endogenous source ags (18-23). Because of the complexity of the network, consensus as to the etiology, pathogenesis, prevention, and treatment of various autoimmune disorders has not yet been reached (24-28). However, the many publications on the topic provide insight into the beneficial aspects of autoimmunity. Certain observations provide encouraging prospects for working with these beneficial aspects (6,7,11,29). For example, there is evidence that by manipulating the immune system, autoimmune disorders could be terminated without employing immunosuppressive and cytotoxic agents (14).

The question is how to present the appropriate ags to the cells of the immune system to evoke favorable responses, (a) specifically downregulating and terminating the disease process in autoimmune disorders, and (b) specifically upregulating lytic aab production to eliminate corrupt cells no matter where in the body they are located as in cancer.

The many attempts at treating autoimmune diseases and cancer by immunological and other means attest to the present reality that the task is not easy. Various methods of ag specific prevention and termination of autoimmune disease causing processes have already been tried (7,8,11). While many of the techniques have achieved prevention, none, whether in experimental animals or in patients with autoimmune diseases, has attained satisfactory outcomes evidenced by discernable experimental or clinical results such as functional or morphological improvements (10,30-34).

Our expertise is in an experimental autoimmune kidney disease called HN (35), which has two variants. The first variant is called active HN. This experimental kidney disease model was described by Heymann and colleagues in 1959 (35). The disease is produced by IP injections of renal tubular ags in Freund's complete adjuvant, causing immune complex (IC) glomerulonephritis associated with proteinuria in a susceptible strain of rats (36). The second variant of active HN is called SPHN, as described recently by us (37). SPHN is induced by injections of renal ags in alum or of aqueous chemically modified renal tubule ags (14,37).

While typical morphological and functional changes can be studied very well in HN, this autoimmune kidney disease cannot be successfully treated by any of various means because of its rapid progression (38-45). SPHN, on the other hand, progresses more slowly, as its name indicates, and therefore it allows more time to investigate various treatment options, including the manipulation of the cells of the immune system by various means (12,15).

In SPHN we have investigated the new vaccination technique that we call MVT. The investigation entailed injecting ICs composed of the nephritogenic ag and specific Immunoglobulin M (IgM) ab directed against it at slight ag excess, at weekly intervals either pre and post induction of SPHN or post induction only. In the former case we managed to prevent the disease from occurring; and in the latter, where the progressive autoimmune kidney disease was already underway, we were able to terminate the immunopathological processes that were responsible for maintaining it (12,15).

The rationale behind successfully preventing and/or terminating autoimmune disease causing and maintaining events is based on previous observations and findings especially of Weir and associates (46,47), and also by Grabar (48) and others. Weir and colleagues have described the presence and role of naturally occurring IgM aabs in the circulation, and have shown conclusively that experimental animals have specific IgM aabs in their circulations against intracytoplasmic organelles. The role of these specific IgM aabs is to assist in the removal of liberated intracytoplasmic components from the circulation following injury to cells by trauma, chemicals, toxic compounds, drugs, and ischemia, or from cells at the end of their lifespan etc. These scientists have subscribed to the view that in a physiological sense we are not tolerant to our intracytoplasmic components, and naturally occurring specific IgM aabs carry out a physiological role by assisting in the removal of cellular waste (47).

By removing intracellular breakdown products quickly and efficiently, IgM aabs serve at least four very important functions:

1. they preclude toxic accumulation of cellular waste;
2. they prevent possible chemical modifications of released intracytoplasmic ags;
3. together with macrophages they assist in the reutilization of large MW subcellular components by breaking them down into reusable small MW components; and
4. they maintain tolerance against "self" components.

Following injections into normal rats of ICs composed of high titred specific IgM abs (directed against the nephritogenic ag) and nephritogenic ags at slight ag excess:

• specific IgM aab cell lines were stimulated to produce elevated levels of IgM aabs against the nephritogenic ag;
• specific IgM aabs were produced rapidly, since rats are not tolerant to the nephritogenic ag (secondary ab response); and
• high levels of circulating IgM aabs were maintained by weekly injections.

By being able to react with the released native autoantigen (aag) from the renal tubules and also with the modified renal ag that causes the disease, these specific IgM aabs (rat anti-renal tubular ag IgM aabs) neutralize and assist in the elimination of both modified and native disease causing and maintaining ags.

4. THE BENEFICIAL ASPECTS OF IMMUNE COMPLEXES IN INITIATING AND MAINTAINING PREDETERMINED IMMUNE RESPONSE OUTCOMES

In experimental animals we have investigated the effect of the injected ICs in redirecting immune response outcomes using tissue derived ags and abs produced in donor animals. While such components are very effective in specifically downregulating and upregulating immune responses against target ags (15), they cannot be employed to treat humans with chronic ailments. To prevent and/or treat human disorders it is necessary to produce the essential ags and abs ex vivo, by available techniques, so as to provide consistently uniform, safe, pure, and potent products.

4.1. The biologics needed to make up the relevant immune complexes to combat human chronic disorders

4.1.1. To prevent or treat/terminate autoimmune diseases

• the aags that contribute to the autoimmune disease will have to be made by various chemical procedures to provide pure chemical compositions equivalent in MW and structural make up etc. of the target aag (49,50);
• the IgM aabs required to prevent or treat autoimmune diseases will have to be made by monoclonal ab techniques (51);

• cancer specific ags will have to be constructed by presently available and by improved future technologies that will be able to provide absolutely pure cancer specific ags (52,53);
• specific lytic abs against cancer specific ags residing on cancer cell surfaces will have to be produced by monoclonal ab techniques (54).

• antigenic component(s) responsible for the invading organism establishing and maintaining a chronic disease must be identified and chemically produced;
• specific abs against the target ag(s) could be produced either by monoclonal ab techniques or in genetically programmed animals able to produce humanized specific abs.

To prevent interference with vitally important immunological cell lines (i.e. suppressing, upregulating, or eliminating them) precise preparatory techniques must be employed to produce specific tissue ag equivalent composition(s) and specific ab(s) against the target ag(s) before implementing the MVT to prevent and treat autoimmune diseases and cancer in humans. Furthermore, such production will have to meet the detailed procedural descriptions and protocol approvals of regulatory bodies. This means that in the future:

• all the target ags (exogenous and endogenous) will have to be produced to meet the highest standards as far as their composition, purity, safety, efficacy etc. are concerned; and
• corresponding abs against the target ags will have to be made by monoclonal or by other production technologies.

The biologics produced by the various techniques should have the same stringent regulatory requirements as for manufactured drugs.

5. PERSPECTIVES

Autoimmune diseases and cancer are presently treated with immunosuppressive and cytotoxic agents (55,56). These medications are nonspecific in their actions and can cause numerous side effects of which infection-caused complications are the worst. Yet these agents have to be employed in the treatment of patients as there is currently no alternative for interfering with the pathogenic autoimmune disease causing immune events that maintain their diseases.

We have noted and described how specific ICs can be produced to correct autoimmune system breakdown related irregularities (12,15). There are two possible major irregularities of the autoimmune system that can lead to major structural and functional disturbances of tissues and organs in the affected host. One of these, which is produced by a pathogenic immune response against self components, causes an autoimmune disease. The other, because pathogenic immune responses against cancer specific ags on cancer cell surfaces do not generally occur, allows unhindered multiplication of cancer cells. In the first instance, pathogenic immune responses against self components cause harm; and in the second instance, pathogenic immune responses against cancer-specific ags terminate cancer cell growth/spread.

Weir and colleagues showed that released intracytoplasmic ags are assisted in their removal by specific IgM aabs (46). These aabs are able to remove native, modified, and native-like (molecular mimicry) ags from the circulation and thereby prevent disease causing pathogenic IgG aab production (12). The beneficial autoimmune events that keep our inner environments free of accidental mishaps are operating at all times under normal conditions. When unusual presentation of self ags, e.g. in SPHN, overwhelms the clearing processes that normally would remove native and modified cell breakdown products, then a genuine manifestation of an autoimmune disease condition can occur by the modified aags inducing and maintaining a pathogenic aab response.

We understand both the immune events that cause an autoimmune disease and those that are responsible for the prevention or termination of autoimmune disease processes in the experimental autoimmune kidney disease model SPHN (12). We have shown how immunopathological events can be prevented prior to the initiation of an experimental autoimmune disease (15), and, following induction of the same disease, how the disease can be specifically terminated by the MVT (15). Prevention and termination of the autoimmune disease was achieved specifically by injections of ICs composed of the target nephritogenic ag and nonpathogenic IgM aabs directed against the target nephritogenic ag at ag excess.

We have clearly outlined the possible application of the MVT for prophylactic and therapeutic use in humans to deal with autoimmune diseases, cancer, and diseases caused by chronic infections. We have stated that in order to have reproducible, safe, and efficacious vaccine components it would be necessary to produce ex vivo purified ags that are in every aspect identical (in MW, chemical composition, structure etc.) to the target ags in question (i.e. the native target ag, cancer specific ag, etc.) Similarly, specific abs against the target ags must also be produced (against specific epitopes on the target ags). Specific IgM abs against native target ags and specific lytic IgG abs against cancer specific ags are necessary to make ICs for the control and termination of autoimmune diseases and cancer, respectively.

The presentation of the ag to the cells of the immune system determines the immune response outcome. With our MVT, having pure ex vivo prepared components assembled into ICs at the right proportions would make it possible to redirect the immune response outcomes specifically without interfering with vitally important immunological cell lines. The vaccination technique initiates and with repeated injections maintains high levels of circulating abs which are made up of the same class of immunoglobulin with the same specificity against the target ag as resides in the inoculum. The MVT reestablishes tolerance to self in certain autoimmune diseases (though memory of the modified ag is retained), and when implemented in various cancers we believe it has the potential of lysing only cancer cells, no matter where in the body they are located.

Several well defined "normal self components" have been described in human and experimental animal studies that are involved in autoimmune disease development (49,57-61), as have cancer specific ags that are involved in cancer development and progression (53,62,63,64). In the future it will be essential, using presently available techniques and soon by more refined procedures, to identify and produce the self-antigenic components that contribute to autoimmune diseases and cancer.

When the technologies for the manufacture of desired normal self-like ags, both autoimmune disease and cancer related, are able to produce uniformly safe, pure, and effective ags, then the future of the MVT can become actualized to prevent, terminate, and cure human autoimmune diseases, cancer, and chronic infection caused ailments.

6. ACKNOWLEDGEMENT

All authors contributed equally to this review article. We also acknowledge the assistance of our research associate, Zoltan B. Kovacs, in computer-related work.

7. REFERENCES

1. B. Coiffier: Rituximab in the treatment of diffuse large B-cell lymphomas. Semin Oncol 29, 30-35 (2002)
doi:10.1053/sonc.2002.30153
PMid:11842386

2. M. S. Czuczman, A. Fallon, A. Mohr, C. Stewart, Z. P. Bernstein, P. McCarthy, M. Skipper, K. Brown, K. Miller, D. Wentling, D. Klippenstein, P. Loud, M. K. Rock, M. Benyunes, A. J. Grillo-Lopez and S. H. Bernstein: Rituximab in combination with CHOP or fludarabine in low-grade lymphoma. Semin Oncol 29, 36-40 (2002)
doi:10.1053/sonc.2002.30152
PMid:11842387

3. D. G. Maloney, B. Smith and A. Rose: Rituximab: mechanism of action and resistance. Semin Oncol 29, 2-9 (2002)
doi:10.1053/sonc.2002.30156
PMid:11842383

4. P. Quartier, B. Brethon, P. Philippet, J. Landman-Parker, F. Le Deist and A. Fischer: Treatment of childhood autoimmune haemolytic anaemia with rituximab. Lancet 358, 1511-1513 (2001)
doi:10.1016/S0140-6736(01)06573-4

5. L. Adorini and F. Sinigaglia: Pathogenesis and immunotherapy of autoimmune diseases. Immunol Today 18, 209-211 (1997)
doi:10.1016/S0167-5699(97)01031-1
PMid:9153950

6. G. T. Nepom: Therapy of autoimmune diseases: clinical trials and new biologics. Curr Opin Immunol 14, 812-815 (2002)
doi:10.1016/S0952-7915(02)00397-7
PMid:12413534

7. M. Peakman and C. M. Dayan: Antigen-specific immunotherapy for autoimmune disease: fighting fire with fire? Immunology 104, 361-366 (2001)
doi:10.1046/j.1365-2567.2001.01335.x
PMid:11899420    PMCid:1783327

8. P. Polakis: Arming antibodies for cancer therapy. Curr Opin Pharmacol 5, 382-387 (2005)
doi:10.1016/j.coph.2005.04.008
PMid:15951239

9. J. Tian, A. Olcott, L. Hanssen, D. Zekzer and D. L. Kaufman: Antigen-based immunotherapy for autoimmune disease: from animal models to humans? Immunol Today 20, 190-195 (1999)
doi:10.1016/S0167-5699(99)01445-0
PMid:10203718

10. H. L. Weiner: Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol Today 18, 335-343 (1997)
doi:10.1016/S0167-5699(97)01053-0
PMid:9238837

11. H. L. Weiner: Oral tolerance, an active immunologic process mediated by multiple mechanisms. J Clin Invest 106, 935-937 (2000)
doi:10.1172/JCI11348
PMid:11032852    PMCid:314352

12. A. Z. Barabas, C. D. Cole, A. D. Barabas and R. Lafreniere: Down-regulation of pathogenic autoantibody response in a slowly progressive Heymann nephritis kidney disease model. Int J Exp Pathol 85, 321-334 (2004)
doi:10.1111/j.0959-9673.2004.00388.x
PMid:15566429

13. A. Z. Barabas, C. D. Cole, A. D. Barabas and R. Lafreniere: Preventative and therapeutic vaccination to combat an experimental autoimmune kidney disease. Biologics: Targets & Therapy 1, 59-68 (2007)

14. A. Z. Barabas, C. D. Cole, A. D. Barabas and R. Lafreniere: Production of Heymann nephritis by a chemically modified renal antigen. Int J Exp Pathol 85, 277-285 (2004)
doi:10.1111/j.0959-9673.2004.00389.x
PMid:15379960

15. A. Z. Barabas, C. D. Cole, A. D. Barabas, A. N. Barabas and R. Lafreniere: Reduced incidence of slowly progressive Heymann nephritis in rats immunized with a modified vaccination technique. Clin Dev Immunol 13, 17-24 (2006)
doi:10.1080/17402520600563758
PMid:16603441    PMCid:2270749

16. A. Z. Barabas, C. D. Cole, A. D. Barabas and R. Lafreniere: Downregulation of a pathogenic autoantibody response by IgM autoantibodies directed against the nephritogenic antigen in slowly progressive Heymann nephritis. Pathol Int 56, 181-190 (2006)
doi:10.1111/j.1440-1827.2006.01944.x
PMid:16634963

17. A. Z. Barabas, C. D. Cole, Z. B. Kovacs and R. Lafreniere: Elevated antibody response by antigen presentation in immune complexes. Med Sci Monit 13, BR119-BR124 (2007)

18. A. Kretz-Rommel, S. R. Duncan and R. L. Rubin: Autoimmunity caused by disruption of central T cell tolerance. A murine model of drug-induced lupus. J Clin Invest 99, 1888-1896 (1997)
doi:10.1172/JCI119356
PMid:9109433    PMCid:508013

19. J. F. Miller and A. Basten: Mechanisms of tolerance to self. Curr Opin Immunol 8, 815-821 (1996)
doi:10.1016/S0952-7915(96)80010-0
PMid:8994861

20. P. S. Ohashi and A. L. DeFranco: Making and breaking tolerance. Curr Opin Immunol 14, 744-759 (2002)
doi:10.1016/S0952-7915(02)00406-5
PMid:12413525

21. S. Romagnani: Regulation of the T cell response. Clin Exp Allergy 36, 1357-1366 (2006)
doi:10.1111/j.1365-2222.2006.02606.x

22. Q. Tang and J. A. Bluestone: Regulatory T-cell physiology and application to treat autoimmunity. Immunol Rev 212, 217-237 (2006)
doi:10.1111/j.0105-2896.2006.00421.x
PMid:16903917

23. A. N. Theofilopoulos: The basis of autoimmunity: Part II. Genetic predisposition. Immunol Today 16, 150-159 (1995)
doi:10.1016/0167-5699(95)80133-2
PMid:7718089

24. K. M. Garza, S. M. Chan, R. Suri, L. T. Nguyen, B. Odermatt, S. P. Schoenberger and P. S. Ohashi: Role of antigen-presenting cells in mediating tolerance and autoimmunity. J Exp Med 191, 2021-2027 (2000)
doi:10.1084/jem.191.11.2021

25. J. J. Lafaille and D. Mathis: Immunological Yin-Yang. Curr Opin Immunol 14, 741-743 (2002)
doi:10.1016/S0952-7915(02)00412-0

26. A. Lernmark: Autoimmune diseases: are markers ready for prediction? J Clin Invest 108, 1091-1096 (2001)

27. B. Ludewig, T. Junt, H. Hengartner and R. M. Zinkernagel: Dendritic cells in autoimmune diseases. Curr Opin Immunol 13, 657-662 (2001)
doi:10.1016/S0952-7915(01)00275-8
PMid:11677086

28. B. Stenglein, G. H. Thoenes and E. Gunther: Genetic control of susceptibility to autologous immune complex glomerulonephritis in inbred rat strains. Clin Exp Immunol 33, 88-94 (1978)

29. S. M. Kerfoot, M. U. Norman, B. M. Lapointe, C. S. Bonder, L. Zbytnuik and P. Kubes: Reevaluation of P-selectin and alpha 4 integrin as targets for the treatment of experimental autoimmune encephalomyelitis. J Immunol 176, 6225-6234 (2006)

30. O. Ben Yehuda, Y. Tomer and Y. Shoenfeld: Advances in therapy of autoimmune diseases. Semin Arthritis Rheum 17, 206-220 (1988)
doi:10.1016/0049-0172(88)90021-2
PMid:3072680

31. J. Golbus and W. J. McCune: Lupus nephritis. Classification, prognosis, immunopathogenesis, and treatment. Rheum Dis Clin North Am 20, 213-242 (1994)

32. W. Heymann, E. P. Kmetec, S. G. Wilson, J. L. P. Hunter, D. B. Hackel and F. Cuppage: Experimental autoimmune renal disease in rats. 240-251 (1963)

33. T. Holmoy and F. Vartdal: The immunological basis for treatment of multiple sclerosis. Scand J Immunol 66, 374-382 (2007)
doi:10.1111/j.1365-3083.2007.01982.x

34. V. K. Ramiya, M. S. Lan, C. H. Wasserfall, A. L. Notkins and N. K. Maclaren: Immunization therapies in the prevention of diabetes. J Autoimmun 10, 287-292 (1997)
doi:10.1006/jaut.1997.0127

35. W. Heymann, D. B. Hackel, S. Harwood, S. G. Wilson and J. L. P. Hunter: Production of the nephritic syndrome in rat by Freund's adjuvant and rat kidney suspension. Proc Soc Exp Biol Med 100, 660-664 (1959)

36. B. Noble, J. B. Van Liew, J. R. Brentjens and G. A. Andres: Effect of reimmunization with Fx1A late in the course of Heymann nephritis. Lab Invest 47, 427-436 (1982)

37. A. Z. Barabas, C. D. Cole, A. D. Barabas and R. Lafreniere: Production of a new model of slowly progressive Heymann nephritis. Int J Exp Pathol 84, 245-258 (2003)
doi:10.1111/j.0959-9673.2003.00358.x

38. A. Z. Barabas, K. James and R. Lannigan: Preliminary observations on the effect of heterologous anti-lymphocytic globulin on autologous immune complex nephritis in rats. Clin Exp Immunol 5, 419-427 (1969)

39. A. Z. Barabas, A. H. Nagi, R. Lannigan and R. A. Womersley: The effect of cortisone treatment on autologous immune complex glomerulonephritis in rats. Br J Exp Pathol 51, 541-546 (1970)

40. D. C. Cattran: Effect of ciclosporin on active Heymann nephritis. Nephron 48, 142-148 (1988)
doi:10.1159/000184894

41. Y. Hasegawa, H. Kaneoka, T. Tanaka, S. Ogahara, T. Matsumae, R. Noda, K. Yoshitake, T. Murata and S. Naito: Suppression of experimental membranous glomerulonephritis in rats by an anti-MHC class II antibody. Nephron 88, 233-240 (2001)
doi:10.1159/000045995

42. L. R. Kupor, D. C. Lowance and J. J. McPhaul, Jr.: Single and multiple drug therapy in autologous immune complex nephritis in rats. J Lab Clin Med 87, 27-36 (1976)

43. W. Matsukawa, S. Hara, F. Yoshida, N. Suzuki, A. Fukatsu, Y. Yuzawa, N. Sakamoto and S. Matsuo: Effects of a new immunosuppressive agent, FK506, in rats with active Heymann nephritis. J Lab Clin Med 119, 116-123 (1992)

44. M. J. Penny, R. A. Boyd and B. M. Hall: Permanent CD8(+) T cell depletion prevents proteinuria in active Heymann nephritis. J Exp Med 188, 1775-1784 (1998)
doi:10.1084/jem.188.10.1775

45. H. Yokoyama, S. Goshima, T. Wada, M. Takaeda, K. Furuichi, K. Kobayashi and H. Kida: The short- and long-term outcomes of membranous nephropathy treated with intravenous immune globulin therapy. Kanazawa Study Group for Renal Diseases and Hypertension. Nephrol Dial Transplant 14, 2379-2386 (1999)
doi:10.1093/ndt/14.10.2379

46. D. M. Weir, R. N. Pinckard, C. J. Elson and D. E. Suckling: Naturally occurring anti-tissue antibodies in rat sera. Clin Exp Immunol 1, 433-442 (1966)

47. D. M. Weir and C. J. Elson: Antitissue antibodies and immunological tolerance to self. Arthritis Rheum 12, 254-260 (1969)
doi:10.1002/art.1780120314

48. P. Grabar: Autoantibodies and the physiological role of immunoglobulins. Immunol Today 4, 337-340 (1983)
doi:10.1016/0167-5699(83)90169-X

49. D. Kerjaschki and M. G. Farquhar: Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats. J Exp Med 157, 667-686 (1983)
doi:10.1084/jem.157.2.667

50. A. V. Oleinikov, B. J. Feliz and S. P. Makker: A small N-terminal 60-kD fragment of gp600 (megalin), the major autoantigen of active Heymann nephritis, can induce a full-blown disease. J Am Soc Nephrol 11, 57-64 (2000)

51. E. Andreakos, P. C. Taylor and M. Feldmann: Monoclonal antibodies in immune and inflammatory diseases. Curr Opin Biotechnol 13, 615-620 (2002)
doi:10.1016/S0958-1669(02)00355-5

52. C. B. Munshi, K. B. Fryxell, H. C. Lee and W. D. Branton: Large-scale production of human CD38 in yeast by fermentation. Methods Enzymol 280, 318-330 (1997)
doi:10.1016/S0076-6879(97)80123-1

53. H. G. Rammensee, T. Weinschenk, C. Gouttefangeas and S. Stevanovic: Towards patient-specific tumor antigen selection for vaccination. Immunol Rev 188, 164-176 (2002)
doi:10.1034/j.1600-065X.2002.18815.x

54. M. Trikha, L. Yan and M. T. Nakada: Monoclonal antibodies as therapeutics in oncology. Curr Opin Biotechnol 13, 609-614 (2002)
doi:10.1016/S0958-1669(02)00348-8

55. R. J. Glassock: The treatment of idiopathic membranous nephropathy: a dilemma or a conundrum? Am J Kidney Dis 44, 562-566 (2004)
doi:10.1016/S0272-6386(04)00868-6

56. A. Perna, A. Schieppati, J. Zamora, G. A. Giuliano, N. Braun and G. Remuzzi: Immunosuppressive treatment for idiopathic membranous nephropathy: a systematic review. Am J Kidney Dis 44, 385-401 (2004)
doi:10.1016/S0272-6386(04)00809-1

57. D. R. Bachinsky, G. Zheng, J. L. Niles, M. McLaughlin, M. Abbate, G. Andres, D. Brown and R. T. McCluskey: Detection of two forms of GP330. Their role in Heymann nephritis. Am J Pathol 143, 598-611 (1993)

58. M. G. Farquhar, A. Saito, D. Kerjaschki and R. A. Orlando: The Heymann nephritis antigenic complex: megalin (gp330) and RAP. J Am Soc Nephrol 6, 35-47 (1995)

59. D. Kerjaschki and M. G. Farquhar: The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proc Natl Acad Sci U S A 79, 5557-5581 (1982)
doi:10.1073/pnas.79.18.5557

60. P. Ronco and H. Debiec: Molecular dissection of target antigens and nephritogenic antibodies in membranous nephropathy: towards epitope-driven therapies. J Am Soc Nephrol 17, 1772-1774 (2006)
doi:10.1681/ASN.2006050497

61. Y. Tsukada, K. Ono, A. Maezawa, S. Yano and T. Naruse: A major pathogenic antigen of Heymann nephritis is present exclusively in the renal proximal tubule brush border--studies with a monoclonal antibody against pronase-digested tubular antigen. Clin Exp Immunol 96, 303-310 (1994)

62. W. Luo, E. Ko, J. C. Hsu, X. Wang and S. Ferrone: Targeting melanoma cells with human high molecular weight-melanoma associated antigen-specific antibodies elicited by a peptide mimotope: functional effects. J Immunol 176, 6046-6054 (2006)

63. G. T. Stevenson: CD38 as a therapeutic target. Mol Med 12, 345-346 (2006)

64. Q. Liu, I. A. Kriksunov, R. Graeff, C. Munshi, H. C. Lee and Q. Hao: Crystal structure of human CD38 extracellular domain. Structure 13, 1331-1339 (2005)
doi:10.1016/j.str.2005.05.012

Abbreviations: aab: autoantibody, aag: autoantigen, ab: antibody, ag: antigen, HN: Heymann nephritis, IC: immune complex, Ig: Immunoglobulin, IgG: immunoglobulin G, IgM: immunoglobulin M, IP: intraperitoneal, MVT: modified vaccination technique, MW: Molecular weight, SPHN: slowly progressive Heymann nephritis

Key Words: Autoantibody, Autoantigen, Autoimmunity, Cancer, Immune Complex, Modified Vaccination Technique, Review