Nonlinear dynamics of immunogenic tumors: Parameter estimation and global bifurcation analysis

Aprominent pathology textbook used in the United States includes an image illustrating the renal histopathology caused by malignant hypertension. The legend describes striking “onion skin” changes of a renal arteriole. Curiously, a sea of mononuclear inflammatory cells surrounding this arteriole is overlooked both in the legend and in the related text. Moreover, nothing regarding inflammation or immune reactions is discussed. This lack of attention to inflammatory cells is, however, not surprising. Although many experimental studies have implicated inflammation in hypertension, these have largely been performed in experimental animals; there is no proof that inflammation contributes to human hypertension. In fact, some anti-inflammatory or immune-suppressing drugs (eg, nonsteroidal anti-inflammatory drugs and cyclosporine) paradoxically cause hypertension in humans, likely via off-target effects. Often the term “inflammation” is used in the context of cardiovascular disease as a catchall referring to nonspecific phenomena, such as elevation of C-reactive protein or the presence of macrophages in a tissue. Most clinicians and investigators find this vague and difficult to understand. Even more puzzling is that many studies now implicate the adaptive immune response, and in particular, lymphocytes, in hypertension and vascular disease. Traditionally, bacterial, viral, or tumor antigens activate this arm of immune defense. As such, it has been hard to imagine how adaptive immunity could be involved in a disease such as hypertension. In this article, we will attempt to address some of these puzzling questions. We will briefly review components of the innate and adaptive immune response, discuss data from many groups, including our own, that suggest that common forms of hypertension are immune mediated, and provide a working hypothesis of how signals from the central nervous system trigger an immune response that causes hypertension.

### General Concepts Regarding Inflammation and Immunity

#### Innate Immunity

The first line of defense against pathogens is the innate immune response. Important components of this system include epithelial …

Inflammation, Immunity, and Hypertension

Extraneuronal cholinergic system in lymphocytes.

Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes.

High blood pressure is present in more than one billion adults worldwide and is the most important modifiable risk factor of death resulting from cardiovascular disease While many factors contribute to the pathogenesis of hypertension, a role of the immune system has been firmly established by a large number of investigations from many laboratories around the world Immunosuppressive drugs and inhibition of individual cytokines prevent or ameliorate experimental hypertension, and studies in genetically-modified mouse strains have demonstrated that lymphocytes are necessary participants in the development of hypertension and in hypertensive organ injury Furthermore, immune reactivity may be the driving force of hypertension in autoimmune diseases Infiltration of immune cells, oxidative stress, and stimulation of the intrarenal angiotensin system are induced by activation of the innate and adaptive immunity High blood pressure results from the combined effects of inflammation-induced impairment in the pressure natriuresis relationship, dysfunctional vascular relaxation, and overactivity of the sympathetic nervous system Imbalances between proinflammatory effector responses and anti-inflammatory responses of regulatory T cells to a large extent determine the severity of inflammation Experimental and human studies have uncovered autoantigens (isoketal-modified proteins and heat shock protein 70) of potential clinical relevance Further investigations on the immune reactivity in hypertension may result in the identification of new strategies for the treatment of the disease

Role of the Immune System in Hypertension

The thymuses of young SHR rats before developing hypertension had reduced numbers of immature T-lymphocytes which were detected by the rosette formation test with guinea pig erythrocytes, whereas the thymuses of other eight rat strains tested contained about 60% rosetting cells. The number of rosetting cells progressively decreased with age. The blastogenic responses to PHA of the SHR rat lymphocytes was depressed to less than one fifth when compared to those of other rat strains including W/Mk rats, the original colony of the SHR rats. Other cell-mediated immune responses, including delayed hypersensitivity, allograft rejections, and a cooperation of T- and B-lymphocytes to produce humoral antibody formation were significantly depressed when compared to those of other rat strains.

Immunological Depression in Spontaneously Hypertensive Rats

Cell-mediated immunity was investigated in spontaneously hypertensive rats (SHR). The thymuses of young SHR rats before developing hypertension had reduced numbers of immature T lymphocytes which were detected by the rosette formation test with guinea-pig erythrocytes in the presence of foetal bovine serum, whereas the thymuses of eight other rat strains tested contained about 60% of rosetting cells. The number of rosetting cells decreased progressively with age. The blastogenic responses to PHA and Con A of the SHR rats' lymphocytes was depressed to less than one-fifth when compared to those of othe rat strains including W/7k rats, the original colony of the SHR rats. Eight-month-old SHR rats showed fewer mitogenic responses than those of 2-month-old SHR rats. Other cell-mediated immune responses, including delayed hypersensitivity, allograft rejections, and a co-operation of T and B lymphocytes to produce humoral antibody formation were depressed significantly when compared to those of other rat strains. Possible mechanisms of immunological depression in the SHR rats in relation to the devleopment of hypertension are discussed.

Immunological depression in spontaneously hypertensive rats.

SUMMARY: The benefits of immunochemotherapy with a penicillin-treated, lyophilized preparation of Streptococcus pyogenes, OK-432 (Picibanil), were reassessed in patients with resected non-small-cell lung cancer through a meta-analysis based on data from 1,520 patients enrolled in 11 randomized clinical trials. All 11 trials were started before 1991, and the subjects had been followed up for at least 5 years after surgery and randomization. In these trials, standard chemotherapy was compared with the same therapy plus OK-432. The endpoint of interest was overall survival, and analysis was based on intent-to-treat population without patient exclusion. Data were analyzed using the Mantel-Haenszel method. The 5-year survival rate for all eligible patients in the 11 trials was 51.2% in the immunochemotherapy group versus 43.7% in the chemotherapy group. The odds ratio (OR) for overall survival was 0.70 (95% CI = 0.56-0.87, p = 0.0010). Analysis of four trials in which central randomization was performed also reconfirmed a significantly longer survival time for the immunochemotherapy group (OR = 0.66, 95% CI = 0.44-1.00, p = 0.049). Based on these results of meta-analysis, it is postulated that postoperative adjuvant immunochemotherapy using OK-432 might improve the survival of patients after resection of non-small-cell lung cancer.

Meta-analysis of adjuvant immunochemotherapy using OK-432 in patients with resected non-small-cell lung cancer.

A strong transplantation resistance to a fibrosarcoma (KMT-17) is induced in syngeneic Wistar King Aptekman/Hok rats after a single s.c. immunization with Friend virus-infected (xenogenized) viable KMT-17 cells. The resistance induced by the repeated immunizations with irradiated Friend virus-infected KMT-17 cells, however, was unexpectedly weaker when compared with that induced by irradiated KMT-17 cells. The immunogenicity of tumor-associated antigen on xenogenized Friend virus-infected KMT-17 cells was correlated with their shortened survival time in the peritoneal cavity after i.p. inoculation, especially in rats preimmunized with xenogenized tumor cells. Furthermore, xenogenized tumor cells producing a medium amount of virus-associated antigen (VAA) but not those producing a large amont of VAA showed an augmented immunogenicity even in normal rats. On the other hand, the tumor-associated antigen immunogenicity was augmented by immunization with xenogenized tumor cells which expressed a relatively small amount of VAA in rats presensitized with VAA. These findings indicate that the immunogenicity of xenogenized tumor cells is augmented by the middle-grade immune responses to VAA produced on xenogenized tumor cells.

https://cancerres.aacrjournals.org/content/canres/43/5/2301.full.pdf

Alteration of Immunogenicity of Xenogenized Tumor Cells in Syngeneic Rats by the Immune Responses to Virus-associated Antigens Produced on Immunizing Cells

A 66-year-old woman was admitted on May 13, 1989, because of an abnormal round shadow in the right hilum on chest X-ray film. Bronchoscopy revealed a stenosis of the right B8 caused by a bulging lesion. An aortogram showed a large meandering bronchial artery and a saccular aneurysm. The aneurysm was about 25 mm in diameter and associated with a bronchopulmonary anastomosis. It was surgically removed by right lower lobectomy. Pathological examination proved that the resected lesion was an arterial aneurysm. Patchy arteriosclerotic change was present in the intima of the aneurysm, but there was no evidence of inflammatory change in the arterial wall and the adjacent alveoli and bronchi. Twenty-six cases of bronchial artery aneurysm have been previously reported in the literature, but this is the first case that appeared as a solitary nodule on conventional chest X-ray.

Takeshi Okayasu

Papers

Immunological Depression in Spontaneously Hypertensive Rats

Immunological depression in spontaneously hypertensive rats.

Meta-analysis of adjuvant immunochemotherapy using OK-432 in patients with resected non-small-cell lung cancer.

Alteration of Immunogenicity of Xenogenized Tumor Cells in Syngeneic Rats by the Immune Responses to Virus-associated Antigens Produced on Immunizing Cells

A Case of Bronchial Artery Aneurysm Demonstrating a Mass Shadow on Chest X-ray Film