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Dive into the research topics where Philip Bardwell is active.

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Featured researches published by Philip Bardwell.


Journal of Immunology | 2009

The Bcl-2 Family Antagonist ABT-737 Significantly Inhibits Multiple Animal Models of Autoimmunity

Philip Bardwell; Jijie Gu; Donna McCarthy; Craig Wallace; Shaughn Bryant; Christian Goess; Suzanne Mathieu; Chris Grinnell; Jamie Erickson; Saul H. Rosenberg; Annette Schwartz; Margaret Hugunin; Edit Tarcsa; Steven W. Elmore; Bradford L. McRae; Anwar Murtaza; Lichun Wang; Tariq Ghayur

The Bcl-2 family of proteins plays a critical role in controlling immune responses by regulating the expansion and contraction of activated lymphocyte clones by apoptosis. ABT-737, which was originally developed for oncology, is a potent inhibitor of Bcl-2, Bcl-xL, and Bcl-w protein function. There is evidence that Bcl-2–associated dysregulation of lymphocyte apoptosis may contribute to the pathogenesis of autoimmunity and lead to the development of autoimmune diseases. In this study, we report that ABT-737 treatment resulted in potent inhibition of lymphocyte proliferation as measured by in vitro mitogenic or ex vivo Ag-specific stimulation. More importantly, ABT-737 significantly reduced disease severity in tissue-specific and systemic animal models of autoimmunity. Bcl-2 family antagonism by ABT-737 was efficacious in treating animal models of arthritis and lupus. Our results suggest that treatment with a Bcl-2 family antagonist represents a novel and potentially attractive therapeutic approach for the clinical treatment of autoimmunity.


Journal of Immunology | 2003

Cutting edge: The G-U mismatch glycosylase methyl-CpG binding domain 4 is dispensable for somatic hypermutation and class switch recombination

Philip Bardwell; Alberto Martin; Edmund Wong; Ziqiang Li; Winfried Edelmann; Matthew D. Scharff

Affinity maturation of the humoral response is accomplished by somatic hypermutation and class switch recombination (CSR) of Ig genes. Activation-induced cytidine deaminase likely initiates these processes by deamination of cytidines in the V and switch regions of Ig genes. This activity is expected to produce G-U mismatches that can be substrates for MutS homolog 2/MutS homolog 6 heterodimers and for uracil DNA glycosylase. However, G-T and G-U mismatches are also substrates of the methyl-CpG binding domain 4 (Mbd4) glycosylase. To determine whether Mbd4 functions downstream of activation-induced cytidine deaminase activity, we examined somatic hypermutation and CSR in Mbd4−/− mice. In this study, we report that CSR, as analyzed by an in vitro switch assay and by in vivo immunizations, is unaffected in Mbd4−/− mice. In addition, the hypermutated JH2 to JH4 region in Peyer’s patch B cells showed no effects as a result of Mbd4 deficiency. These data indicate that the Mbd4 glycosylase does not significantly contribute to mechanisms of Ab diversification.


Molecular Immunology | 2001

Testing the reverse transcriptase model of somatic mutation

Stephen Z Sack; Philip Bardwell; Matthew D. Scharff

Somatic hypermutation of the variable (V) regions of rearranged immunoglobulin genes leads to antibody affinity maturation. Although this process has been extensively studied, the mechanisms responsible for these multiple point mutations are still elusive. One mechanism that was proposed over 10 years ago by Steele and Pollard was that an intrinsic reverse transcriptase (RT) copies the nascent mRNA creating the large number of observed point mutations due to its high error rate. A cDNA copy of the mutated V region would then replace the endogenous DNA through a gene conversion-like event, thus integrating these point mutations into the genome. This model of hypermutation would account for the very high mutation rate, the presence of hotspots, strand bias, the requirement for transcription and localization of mutation within the immunoglobulin V region. Using AZT and ddC to inhibit endogenous RTs, we have assayed for somatic mutation using a murine in vivo model. Somatic mutation occurred at similar frequencies and with the same characteristics with or without treatment of RT inhibitors, suggesting that standard reverse transcription is not required for antibody V region hypermutation in the mouse.


Journal of Immunological Methods | 2002

Mutation detection of immunoglobulin V-regions by DHPLC

Philip Bardwell; Alberto Martin; Matthew D. Scharff

One of the key features in the affinity maturation of antibodies is somatic hypermutation of the variable regions of immunoglobulin genes. The mutations that occur in immunoglobulin genes are detected by direct sequencing of cloned polymerase chain reaction (PCR) products. The frequencies of mutations in vivo are generally high enough to provide sufficient numbers of point mutations in order to generate large databases that can be analyzed in various ways. Recently, the mechanisms of variable (V)-region hypermutation have been studied in tissue culture systems and transgenic mice where mutation occurs at frequencies that are approximately 10-fold lower than the estimated in vivo rate. Identifying mutations by brute force sequencing of PCR products in comparative studies is limiting when trying to determine if there are statistically significant differences. Here we describe a high throughput technique that can facilitate the identification of immunoglobulin V-regions that contain one or more mutations before sequencing. This technique, known as denaturing high-performance liquid chromatography (DHPLC), utilizes a standard HPLC apparatus with a column that binds double-stranded DNA (dsDNA). In this study, we have successfully detected approximately 90% of previously sequenced mutated V-regions by DHPLC. Our results show that we were able to detect mutations throughout a 321-base pair (bp) region of the Ricin 45 immunoglobulin (Ig) V-region. Also, with the use of this assay, we have been able to detect mutations in multiple clones of different immunoglobulin genes.


Protein & Cell | 2018

Potent and conditional redirected T cell killing of tumor cells using Half DVD-Ig

Philip Bardwell; Matthew M. Staron; Junjian Liu; Qingfeng Tao; Susanne Scesney; Gail Bukofzer; Luis E. Rodriguez; Chee-Ho Choi; Jennifer Wang; Qing Chang; Feng Dong; Cherrie K. Donawho; Jieyi Wang; Christine Grinnell; Edit Tarcsa; Charles W. Hutchins; Tariq Ghayur; Jijie Gu

Novel biologics that redirect cytotoxic T lymphocytes (CTLs) to kill tumor cells bearing a tumor associated antigen hold great promise in the clinic. However, the ability to safely and potently target CD3 on CTL toward tumor associated antigens (TAA) expressed on tumor cells remains a challenge of both technology and biology. Herein we describe the use of a Half DVD-Ig format that can redirect CTL to kill tumor cells. Notably, Half DVD-Ig molecules that are monovalent for each specificity demonstrated reduced non-specific CTL activation and conditional CTL activation upon binding to TAA compared to intact tetravalent DVD-Ig molecules that are bivalent for each specificity, while maintaining good drug like properties and appropriate PK properties.


Archive | 2011

Tri-variable domain binding proteins and uses thereof

Tariq Ghayur; Chengbin Wu; Hua Ying; Carrie Goodreau; Philip Bardwell


Journal of Immunology | 1998

Rheumatoid Factor Specificity of a VH3-Encoded Antibody Is Dependent on the Heavy Chain CDR3 Region and Is Independent of Protein A Binding

Meilin Zhang; Adrian Majid; Philip Bardwell; Chris Vee; Anne Davidson


Archive | 2007

Method of preventing or treating organ, hematopoietic stem cell or bone marrow transplant rejection

Philip Bardwell; Tariq Ghayur; Jijie Gu; Ingela Vikstrom; Andrew M. Lew; David Matthew Tarlinton; Emma M. Carrington; David Ching Siang Huang


Archive | 2014

Methods and compositions for modulating an immune response

Chee-Ho Choi; Qingfeng Tao; Philip Bardwell; Tariq Ghayur


Archive | 2008

METHOD OF TREATING ARTHRITIS

Philip Bardwell; Tariq Ghayur

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Tariq Ghayur

University of California

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Chee-Ho Choi

University of Massachusetts Amherst

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Matthew D. Scharff

Albert Einstein College of Medicine

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Alberto Martin

Albert Einstein College of Medicine

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Anne Davidson

The Feinstein Institute for Medical Research

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Cherrie K. Donawho

University of Texas MD Anderson Cancer Center

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Edmund Wong

Albert Einstein College of Medicine

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