MP4006 (n=1791)
`
`HIGHLY CONFIDENTIAL(cid:173)
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`PTX0029
`
`MEDA_APTX02845997
`
`PTX0029-0000 1
`
`1
`
`CIP2052
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

`

`IFN-y—induced apoptosis of keratinocytes
`in patients with atopic dermatitis
`
`upregulated in
`AD skin
`
`/
`
`.0 C}
`
`skimH1 skinH2 SkinH3 skinH13
`
`.t
`
`skinA01Ni..3kmA132at0 skinmaNi.A
`
`{‘3a
`
`skinso:i. SkinLskinseaL
`
`sion of multiple apoptosis-related and IFN—y—inducible genes is
`responsible for apoptosis of keratinocytes, leading to eczema, and
`influences the development of chronic skin inflammation in pa-
`tients with atopic dermatitis. The study outlines the complexity of
`atopic dermatitis as a heterogeneous and multifactorial disease and
`proposes several potential novel genes that might play a role in the
`pathogenesis and can be used to develop novel treatment modali—
`ties in patients with atopic demiatitis.
`
`Nine genes that are upreg ulated in the skin from patients with atopic dermaA
`titis (AD) can be induced by lFN-y in keratinocytes (KCS).
`
`and defines a novel system for studies of CD8+ Ticell regulation.
`
`Naive T lymphocytes jump-start allergic
`
`responses
`
`mgdxum
`of;
`
`boiled Papaln
`
`Papain
`1.052 3
`
`papayaederivcd food allergen p pain or‘parasttieilllectionyare
`associated with basophil recruitment to draining lymph nodes.
`Basophils have the capacity to present antigen to naive T cells and
`promote THZ differentiation directly or indirectly through
`production of the cytokine IL—4. How papain induces basophil
`migration to lymph nodes is unknown. In this issue Liang et al
`(p 1377) elucidate a pathway in mice in which naive T lympho—
`cytes first encounter and recognize papain through protease-
`activated receptor 2 (PARZ) and initiate T32 differentiation. When
`mice were injected subcutaneously with papain, naive T cells
`produced hasophil—attracting chemoattractant cytokines and IL—4
`(see Figure), leading to basophil accumulation in the lymph nodes.
`A subset of naive human peripheral blood T lymphocytes
`
`Papain stimulates H4 gene expression (left) and |L-4 production (repre-
`sented by green fluorescent protein, right) in naive CD4 T lymphocytes.
`
`expressed PARZ and responded to papain in a manner similar to
`their murine counterparts. These results suggest that there is an
`allergen recognition pathway mediated by naive T lymphocytes
`that express PAR2, which provide an early source of IL—4 upstream
`of basophils and antigen—restricted THZ differentiation.
`Furthermore, PARZ antagonism can be explored for the treatment
`of allergic disease.
`
`Cytomegalovirus and
`_
`6d...
`,,
`
`a
`
`Ions.
`
`p
`
`common variable
`
`Patients with common variable immunodeficiency (CVID) ex-
`perience a spectrum of alterations in cellular immunity. Marashi
`et al (p 1349) profiled the global effect of cytomegalovirus (CMV)
`infection on immune effector cells in patients with CVED and im—
`plicated CMV as the driving force behind the CD4/CD8 ratio inver—
`sion characteristic of these patients. A subset of patients with GVID
`experience debilitating inflammatory disease, and the study focused
`on these patients to show that expansions of CMV—specific late
`
`FN-
`.
`m llt
`9.1
`_
`a
`N
`and TNF-OL were important tor this proliferation. The authors pre-
`viously detected CMV antigens at inflammatory sites in these pa—
`tients, providing a plausible explanation for the persistent antigenic
`stimulation that is presumably required to drive this proliferative
`phenotype. Infliximab and ganciclovir have been used to manage
`OWE—related inflammatory disease, and this study provides a
`compelling rationale for a controlled clinical trial. More broadly, it
`emphasizes the global effect of CMV infection on cellular immunity
`
`HIGHLY CONFIDENTIAL-
`HIGHLY CONFIDENTIAL -
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`2
`
`MEDA_APTX02845998
`MEDA_APTX02845998
`
`PTX0029-00002
`PTX0029-00002
`
`2
`
`