Vol 6-2 Original Research Article

Immunogenetic Association of 127 Human Leukocyte Antigen (HLA) Alleles with 30 Cancers in Continental Western European Countries

Apostolos P. Georgopoulos1,2,3,4*, Lisa M. James1,2,3

1The HLA Research Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

2Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

3Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

4Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Human leukocyte antigen (HLA) genes have been associated with susceptibility and protection against a number of cancers. Here we used an immunogenetic epidemiological approach to evaluate the overall influence of 127 HLA Class I and II alleles on 30 types of cancer. We found a preponderance of protective alleles (negatively correlated with cancer prevalences), especially for HLA Class I. Of the 30 cancers investigated, 13 were associated with mostly protective HLA effects whereas only 2 were associated with mostly susceptibility HLA alleles. Taken together, these findings highlight the broad influence of HLA on cancer and the complexity of HLA-cancer associations.­­

DOI: 10.29245/2578-3009/2022/2.1227 View / Download Pdf
Vol 6-1 Original Research Article

Experimental Autoimmune Encephalomyelitis Animal Models Induced by Different Myelin Antigens Exhibit Differential Pharmacologic Responses to Anti-Inflammatory Drugs

Yuxi Yan1#, Quan Zhao1#, Ya Huang1, Janine Y. Yang2, Jie Zou1, Chunxia Ao1, Xiaojuan Chai1, Renhong Tang1 and WenQing Yang1*

1State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, Jiangsu, China.

2Massachusetts Eye and Ear, Harvard Medical School, USA

Background and objective

Experimental autoimmune encephalomyelitis (EAE) is the most commonly used model for studying autoimmune-mediated myelin degradation in multiple sclerosis (MS). Here, we evaluated the pharmacologic responses of several anti-inflammatory drugs with varying mechanisms of actions (MOAs) using EAE models induced by different MOG immunogens to reveal differential pharmacologic characteristics of the disease models and provide a general guidance in animal model selection for MS research.

Methods

The pharmacologic responses of anti-inflammatory drugs with different mechanisms of actions (MOAs) were evaluated using EAE models induced by either myelin oligodendrocyte glycoprotein p35-55 (MOG35-55)  or p1-128 (MOG1-128). EAE animal models were developed in mice with C57BL/6 background. The animals were treated with different anti-MS medications, including 3 B cell-mediated agents and 2 T cell-mediated agents, respectively. Clinical symptoms were monitored and scored, and pharmacodynamic markers including cytokine secretion, inflammatory cell infiltration, and demyelination in spinal cord were analyzed.

Results

In MOG35-55 peptide-induced EAE model, T cell modulating agents Secukinumab and Fingolimod significantly alleviated clinical symptoms, while B cell-depleting agents, BTK inhibitors PRN2246 and Telitacicept, displayed minimal therapeutic effects or even exacerbated disease progression. In contrast, both T cell-modulating agents and B cell-depleting agents ameliorated disease severity in MOG1-128-induced EAE model. T cell and B cell infiltration in spinal cord increased with disease progression in MOG1-128-induced EAE model.

Conclusions

Our results demonstrated that induction of EAE by different myelin antigens resulted in differential pharmacologic responses to drugs with specific MOAs. The MOG35-55 peptide-induced EAE model only responded to T cell-modulating drugs, whereas the MOG1-128 protein-induced EAE model exhibited therapeutic sensitivity to both T cell- and B cell-modulating agents. These data suggest the MOG35-55 peptide-induced EAE model is suitable for assessing T cell-modulating agents while MOG1-128 protein-induced model can be employed to evaluate both T cell- and B cell-modulating agents.

DOI: 10.29245/2578-3009/2022/1.1231 View / Download Pdf
Vol 6-1 Commentary

Commentary: Decellularized Versus Conventional Cryopreserved Pulmonary Allografts for Right Ventricular Outflow Tract Reconstruction During the Ross Procedure

Dave M. Mathew BS, Kathryn S. Varghese BS, Serena M. Mathew, Roshan Pandey, Sarah Ahmed, Stephanie A. Salazar BS, Dillon O. Rogando BS, Peter J. Fusco BS, Kenneth H. Levy BS, Adham Ahmed BS*

City University of New York (CUNY) School of Medicine, New York, New York

DOI: 10.29245/2578-3009/2022/1.1229 View / Download Pdf
Vol 6-1 Short Communication

HBsAg and Immune Competency; is HBsAg a Mere Biomarker or a Therapeutic Target for Chronic Hepatitis B?

Jin Hyang Kim1,2#, Grace Park3, Bhavna Paratala1,4, Rene Rijnbrand1,5, Michael J. Sofia1 and Hie-Won Hann3*

1Arbutus Biopharma Corporation, 701 Veterans Circle, Warminster, Pennsylvania, 18974, US

2Current address: Bristol Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ 08648, US

3Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, US

4Current address: Adaptimmune LLC, 351 Rouse Boulevard, Philadelphia, PA 19112, US

5Current address: Dicerna Pharmaceuticals, 33 Hayden Ave, Lexington, MA 02421

Hepatitis B virus (HBV) is a main cause of hepatocellular carcinoma (HCC) development. Although controversial, it is increasingly recognized that the immune responses directed against infected hepatocytes drive hepatic inflammation and tissue injury. Here we extended our previous findings to report that serum surface antigen (HBsAg) levels are a biomarker not only for HBV-specific immunity, but also for ongoing non-specific immune activation. We found that the HBV-specific T cell responses in patients with HBsAg < 500 IU/mL, while significantly higher than those in patients with HBsAg > 50,000 IU/mL, had already reached levels comparable to patients with seroclearance. In addition, lower HBsAg levels were associated with reduced non-specific immune activation, while no further reduction was observed with HBsAg < 500 IU/mL. We propose HBsAg is a therapeutic target for reducing inflammation.

DOI: 10.29245/2578-3009/2022/1.1226 View / Download Pdf
Vol 6-1 Original Research Article

Plasmacyte Heterogeneity of Lame Ducklings

Paul F. Cotter

Cotter Laboratory, Arlington, MA, 02476, USA

The aim is to describe the array of plasmacytes (PC), cells known as the source of antibody, occurring in the bone marrow (BM) of lame ducklings. The method is by a light microscopic examination of touch preparation slides made from femur samples and stained with Wright-Giemsa. Samples were obtained on site at commercial farms where slide preparations were made; reducing the possibility that observations are technical artifacts.

The results: indicate that PC occur in a multitude of sizes, shapes, nuclear/cytoplasmic (N/C) ratios, ploidy, and nuclear and cytoplasmic conditions. Normal PC are illustrated first, followed by atypical forms. Some PC are presented in the context of neighboring BM cells of the granulocyte, erythrocyte, and reticulum cell (histiocyte) series.

More than 100 Mott-type PC were measured in a single sample from a 13-day lame duck; and several distinct forms were identified. Size, as measured by their longest axis, varied from 6.1 to 28 μm and it appears to be normally distributed. Moreover, N/C ratios were distributed across a three-fold range (0.3 – 0.9) indicating Mott phenotypes can occur at multiple developmental stages. Motts differed in Russell Body (RB) size, and nuclear condition. A novel Mott type, “orb” form, with partially lysed nuclei is also described.

PC were often found in association with giant granulated histiocytes (ggh) and non-granulated giant histiocytes (gh). Other atypical forms are “hand-mirror” PC, trinucleate and binucleate PC resembling cells seen in multiple myeloma (MM) and lymphomas.

 Collectively these PC variants constitute “reactive plasmatosis” (RP) likely arising as a consequence of the presence of various bacteria including Streptococcus and E. coli.            

The conclusions: It is demonstrated that RP as occurs in lame ducklings suffering from bacterial infections, provides a unique theater for the study of PC variability. Atypical PC, some resembling neoplastic types, were common in RP BM. The significance of the study relates to the importance of PC in disease and immunity; therefore, these observations should interest those who specialize in these areas. They expand the knowledge of avian plasmacyte morphology.

DOI: 10.29245/2578-3009/2022/1.1225 View / Download Pdf