New vaccination technology for endogenous antigen-derived ailments.

Neither autoimmune disorders nor cancer can be prevented with treatment modalities that are currently available. These diseases are generally treated with immunosuppressive agents and cytotoxic drugs, both of which can cause numerous side effects. However, scientific evidence now exists to suggest that such endogenous antigen-derived ailments can be controlled and even terminated by immunological approaches. Both autoimmune disorders and cancer can progress into chronic, irreversible conditions because of the abnormal presentation of endogenous antigens to the cells of the immune system. By appropriate regulation of the autoimmune system, both types of ailments could be curable. This feature review describes various autoimmune events that may occur both to the benefit and the detriment of the host, and highlights a new vaccination technique against slowly progressive Heymann nephritis. This modified vaccination technique holds promise in the prevention and cure of autoimmune system-related disorders. The vaccination has been employed both against endogenous antigen-induced diseases (autoimmune disorders and cancer) and against exogenous antigens. In each study performed to date, the technique has been demonstrated to induce specific, predetermined immune response outcomes.

Antibody-initiated beneficial and harmful immune responses.

A critical function of the immune system is to maintain tolerance to self by corrective immune responses throughout life, including preventing or correcting changes that may interfere with organ function and architectural integrity. These changes have two broad categories, namely (1) exogenous antigen-induced mishaps (e.g., due to bacterial, viral or fungal infections) and (2) endogenous antigen-caused ailments initiated by modified self-antigens derived from damaged organs following exposure to smoke, certain drugs, chemicals, infectious agents, radiation, etc., resulting in autoimmune diseases or cancer. In some cases, cells of the immune system are unable to respond with a corrective antibody response. For example, presentation of a modified self-antigen can initiate a pathogenic IgG immune response, thereby causing an autoimmune disease. Furthermore, if cancer-associated antigens are not appropriately presented to the cells of the immune system, there is failure to mount a specific pathogenic lytic IgG autoantibody response for recognition and elimination of cancer-associated antigens, and as a consequence, the cancer continues to proliferate.The third vaccination technique that we have developed and designated a modified vaccination technique (MVT) is able to correct these immunological mishaps. The premise of the MVT is that it can prevent both exogenous (infectious and contagious diseases) and endogenous (autoimmune diseases and cancer) antigen-caused diseases, as well as terminate established diseases. Therefore, by exploiting the immune system's natural abilities to make corrective responses, it has both prophylactic and therapeutic actions, with minimal side effects.

A modified vaccination technique for the prevention and treatment of an experimental autoimmune kidney disease.

The main purpose of this article is to introduce a promising new vaccination technique and to outline its efficacy and safety as demonstrated in an experimental autoimmune kidney disease. We have found that antigen (AG)-specific downregulation and/or upregulation of immune responses can be achieved by injections of immune complexes (ICs) which contain prepackaged information. This result is attained with the new vaccination method, a method developed in our laboratory which we have called "modified vaccination technique" (MVT). This MVT not only enables the prevention of pathogenic autoimmune events leading to the development of an experimental autoimmune kidney disease; it also allows, with equal effectiveness, therapeutic intervention to terminate the disease. With an injected IC containing predetermined immune response-inducing components, the process effectuates a specific antibody information transfer conferring advantages that go beyond its prophylactic and therapeutic applicability. Its specificity can induce a precise immune response to correct mishaps, for example, in conditions where the immune system overreacts to an autologous antigen or fails to recognize unwanted self (as in autoimmune disorders, cancer, etc.) Preformed ICs are nontoxic and nonirritant, evoke a predetermined antibody response without the use of adjuvants, cause no disturbance in the overall regulatory function of the immune system, and produce no side effects. We firmly believe that proper implementation of the MVT will be able to induce and maintain specific preventive and/or curative responses in a way that is both natural and more effective in patients with chronic ailments presently treatable only with drugs.

Tolerance, loss of tolerance and regaining tolerance to self by immune-mediated events.

Autoimmunity has both beneficial and harmful aspects. Beneficial aspects include: (1) removal of released intracytoplasmic antigens (ags) (cells at the end of their life span or damaged by outside agents) by specific nonpathogenic IgM autoantibodies and mononuclear cells and (2) recognition and elimination of cancerous cells. In contrast, harmful aspects include: (1) mounting a pathogenic autoimmune response against a tissue-derived ag, a 'modified self,' resulting in autoimmune disease and (2) inability to recognize and eliminate a cancerous clone. The immune system continuously faces internal and external influences; however, even when it is compromised or overwhelmed, it will still endeavor to regain and maintain tolerance to self. To promote this, we developed a 'modified vaccination technique' (MVT) (described as the third vaccination method after active and passive immunizations). It has two components: purified exogenous/endogenous ag (i.e., target ag) and a high-titer-specific antibody (ab) against the target ag made into an immune complex (IC) with predetermined immune-inducing components. The MVT works by ab information transfer (production of same class of immunoglobulin with the same specificity against the target ag that is present in the vaccine), thereby re-establishing tolerance to self (caused by exogenous/endogenous ags) following repeated administration of appropriate ICs. This vaccination technique can be used both prophylactically and therapeutically, and it mimics the immune system's natural abilities to respond to corrective information specifically, rapidly, safely and with minimal side effects and makes this approach a novel solution for many disorders that are difficult or impossible to cure or manage.

Antigen-specific down-regulation of immunopathological events in an experimental autoimmune kidney disease.

Heymann nephritis (HN) is an experimental autoimmune disease of rats characterized by immune-complex (IC) depositions on the epithelial side of the glomerular basement membrane (GBM) and by proteinuria. Several forms of HN have been produced by various investigators, but one thing has been common to all of them, namely their inducement by the development of pathogenic IgG autoantibodies (aabs). The aim of this review is to describe how pathogenic IgG aab production (which initiates and maintains the disease) in slowly progressive HN (SPHN) can be specifically terminated by injections of ICs made up of native rat renal tubular antigens and IgM antibodies directed against them.

Regaining tolerance to a self-antigen by the modified vaccination technique.

Autoimmune diseases are initiated and maintained by complex immunopathological processes in environmental and genetic factor predisposed patients. In certain autoimmune diseases, the etiologies and pathogenesis of the conditions are quite well understood; yet in others, controversy surrounds as to why and how auto-injurious processes start. Clinical and laboratory examinations reasonably well define the state of progression/remission of an autoimmune disease and allow treatment according to observed findings. However, none of the presently employed treatment options are specific. In fact, they are all nonspecific in their actions and have undesirable side effects. Over the years, experiments carried out in animals have shed light on the complex immunopathological processes which contribute to disease development and progression. At least one experimental autoimmune kidney disease-which we shall describe-helps to understand how pathogenic autoimmune responses can be terminated specifically, without side effects. Since the new vaccination method-that we call modified vaccination technique-was successfully implemented in an experimental autoimmune disease model called slowly progressive Heymann nephritis for the termination of pathogenic immune responses by a target antigen-specific treatment modality, we shall highlight its use in providing insight to physicians and autoimmunologists for its future implementation in human autoimmune diseases.

Immunopathological events initiated and maintained by pathogenic IgG autoantibodies in an experimental autoimmune kidney disease.

The experimental models of Heymann nephritis (HN) and slowly progressive Heymann nephritis (SPHN) give us rare opportunities to investigate the etiologies and pathogenesis of two immunopathological processes in rats leading to: (1) autoimmune disease, where the autoimmune disease HN and SPHN is initiated and maintained by cross-reactive pathogenic IgG autoantibodies (aabs) directed against the renal proximal convoluted tubules' brush border (BB) cells - where the nephritogenic antigen (ag) is produced and localized - damaging and releasing BB associated nephritogenic ag into the circulation which in turn contributes to continuation of the autoimmune disease; and (2) immune complex glomerulonephritis, where the glomerular injury is initiated, proceeding into a chronic progressive disease by depositing immune complexes (ICs) - made up of a glomerular epithelial cell produced endogenous nephritogenic ag and the developing pathogenic IgG aab directed against the nephritogenic ag, and complement components - on the epithelial side of the glomerular basement membrane. We also observed how the normally functioning immune system is able to avert autoimmune disease developments by circulating specific non-pathogenic IgM aabs clearing the system of intracytoplasmic ags released from cells at the end of their life spans or following damage by toxic agents. We also described how an autoimmune disease SPHN can be prevented and when present terminated by the implementation of a new vaccination technique we have developed and call modified vaccination technique. By increasing the specific IgM aab production against the native nephritogenic ag - by injecting ICs made up of: [nephritogenic ag X homologous anti-nephritogenic ag IgM ab] in slight ag excess into SPHN rats - pathogenic IgG aab producing native and modified nephritogenic ags were removed from the circulation and termination of the autoimmune disease causing immune events was achieved. Even though HN and SPHN are not well-known disease models, their studies are important because the etiologies and pathogenesis of two conditions - that can also occur in humans, namely autoimmune diseases and membranous glomerulonephritis - can be simultaneously investigated.

The role of autoimmunologists in investigating and treating autoimmune disorders.

The role of an autoimmunologist is to investigate and cultivate knowledge of normal and abnormal immune responses against self, which includes developing practical know-how to manipulate autoimmune activity and direct positive autoimmune outcomes. Where a subject develops an abnormal immune response directed against normal self, resulting in an autoimmune disease, the specialist should be able to diagnose the problem and institute an appropriate treatment. Obversely, where a subject lacks an immune response against cells bearing antigens that are abnormal or not quite self, i.e., cancer cells, the specialist should ideally be able to institute a specific cancer cell killing regimen. Essentially there are two beneficial and two harmful aspects of autoimmunity autoimmunologists should be familiar with. The beneficial aspects are the immune responses that assist in the clearance of cellular breakdown products and the elimination of cancer cells. The harmful aspects consist of immune responses, or lack thereof, that manifest in autoimmune disorders, i.e., autoimmune diseases and cancer. Recent medical discoveries, especially the modified vaccination technique developed by the Barabas research group, show great promise in both preventing and curing autoimmune disorders by utilizing the immune system's natural abilities to re-establish normal health.

Correcting autoimmune anomalies in autoimmune disorders by immunological means, employing the modified vaccination technique.

Our research group has developed a new vaccination technique in experimental animals that has the potential of correcting autoimmune anomalies in humans such as autoimmune disorders, cancer, and chronic infections, both prophylactically and therapeutically. The vaccination method is called Modified Vaccination Technique (MVT). The MVT necessitates the introduction of a purified target antigen (ag) and a specific antibody (ab) against the target ag in the form of immune complex (IC) to evoke the desired immune response outcome by ab information transfer in the injected recipient. The injected IC produces the same class of ab in the host, with the same specificity against the target ag, as resides in the inoculum. The MVT promises to provide a means of upregulating beneficial immune events and downregulating undesirable immune responses in individuals, thereby re-establishing normalcy/tolerance to self.

Preventing and treating chronic disorders using the modified vaccination technique.

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.

Elevated antibody response by antigen presentation in immune complexes.

BACKGROUND: Active immunization techniques against exogenous source antigens (ags - such as bacteria, virus) proved to be successful in preventing many acute infectious diseases from occurring in a susceptible population. However, an active immunization technique that could be employed both prophylactically and therapeutically has so far not been described. We have developed a new vaccination technique that employs specific immune complex (IC) containing components which is able to redirect immune-response outcomes in both preventative and curative regimens in an experimental autoimmune kidney disease. The technique with appropriate modifications was assessed using an exogenous ag in our present experiment. MATERIAL/METHODS: We prepared an exogenous ag on a HiTrap affinity column and injected it by five different vaccination techniques into rats. Antibody (ab) responses against the ag were evaluated by ELISA. Statistical analysis assessed possible significant differences in ab responses. RESULTS: The most powerful immune response was initiated following intraperitoneal (IP) injections of normal rabbit immunoglobulin G (nRIgG) in Freund's complete adjuvant (FCA). The second most powerful immune response was evoked when the same ag (nRIgG) was injected in the form of IC at ag excess. CONCLUSIONS: 1. Induction of a powerful ab response, without the use of an adjuvant, can be achieved in rats injected with ICs. 2. IC is non-toxic, non-irritant, and able to initiate the production of the same class of immunoglobulin with the same specificity/function that resides in the inoculum.

Effect of rat kidney fraction 3 (rKF3) antigen and specific IgM antibody against rKF3 on the progression of slowly progressive Heymann nephritis.

The aim of the present study was to find out if specific IgM (M) antibody (directed against rat kidney fraction 3 (rKF3)) or rKF3 antigen were able to influence disease progression in an experimental autoimmune kidney disease called slowly progressive Heymann nephritis (SPHN). The level of circulating autoantibodies (aabs) and the morphological and functional changes to the kidney were studied in six groups of rats. All of the treatment components (except post-treatment with M) used in the SPHN pre- and post-treated rats and post-treated-only rats had measurable beneficial effects (even during restimulation with the chemically modified renal antigen, 22 weeks after the induction of the disease) as demonstrated by diminished pathogenic IgG aab production, less severe kidney lesions, and proteinuria reductions. The injected rKF3 minimized progression best in this experiment, especially when administered in a pre- and post-treatment regimen. It is thought that the effect of rKF3 in the reduced progression of SPHN was due to increased production of specific IgM aabs, which in turn limited pathogenic aab production and continuous buildup of immune complexes in the glomeruli by facilitating removal or blockage of nephritogenic autoantigens from the circulation.

Downregulation of a pathogenic autoantibody response by IgM autoantibodies directed against the nephritogenic antigen in slowly progressive Heymann nephritis.

The purpose of the study was to find out if a new modified vaccination technique would be effective in downregulating immunopathological events during the course of an experimental autoimmune kidney disease (which is morphologically and functionally similar to Heymann nephritis) called 'slowly progressive Heymann nephritis' (SPHN). We have shown that the pathogenic IgG autoantibody (aab)-induced experimental autoimmune kidney disease process can be downregulated early on as well as during the chronic progressive phase, when rats were restimulated. The IgM aab, resulting from stimulation by immune complexes made up of rat kidney fraction 3 (rKF3) antigen and rat anti-rKF3 IgM antibody in antigen excess (MIC), can greatly diminish pathogenic aab production by removing or blocking nephritogenic antigens. Reduced IgG aab production limits the formation of damaging immune complexes (IC) in the glomeruli and development of proteinuria. At the end of the experiment 60% and 80% of the MIC-treated groups had no pathogenic IgG aab in their circulation, while all the untreated SPHN rats had high levels of IgG aab associated with disease progression manifesting in increased proteinuria and severe immune complex glomerulonephritis.