Search

The recent approval of the first commercial peanut oral immunotherapy formulation ushered a new era of clinical food allergy treatment. With different options for peanut immunotherapy available, it is important review the evidence of efficacy, risks, and unique considerations for the individual modalities. Oral immunotherapy (OIT), epicutaneous immunotherapy (EPIT), and sublingual immunotherapy (SLIT) for peanut allergy have risen as possible treatments for peanut allergy. Numerous studies indicate that OIT effectively desensitizes by increasing the amount of peanut protein than can be consumed without symptoms. While this desensitization is to increased amounts of peanut protein when compared to SLIT or EPIT, OIT appears to have greater risk for anaphylaxis and other adverse events. EPIT has the unique benefit of a single-dose patch without the need for in-clinic visits for dose escalation, and it bypasses the oral route which may be advantageous in certain patients. The impact of peanut immunotherapy on health-related quality of life is not well studied and current data is conflicting, but suggests that improvement in certain domains of QOL, especially for caregivers of children with peanut allergy, may be an important target for immunotherapy. This review focuses on the data for efficacy, safety, and tolerability of OIT, SLIT, and EPIT with the aim of presenting information that will assist allergy practitioners in choosing an immunotherapy modality when indicated.

The most clinically relevant food allergens are cow’s milk, hen’s egg, peanut, tree nuts, wheat, soy, fish, shellfish, and seeds. Heat-stable food allergens have molecular characteristics that enhance protein stability and gastrointestinal absorption and thus are more likely to cause systemic reactions on ingestion. In contrast, heat-labile food allergens lack these characteristics and do not typically elicit reactions if sufficiently altered by heat or acid. Immunologic cross-sensitization between food allergens is more common than clinical cross-reactivity. However, certain groups of food allergens, such as tree nuts, fish, and shellfish, are associated with high rates of clinical cross-reactivity. Knowing the rates of clinical cross-reactivity is important when providing guidance to patients with food allergy and families on what foods can be safely added to the diet and what foods should be avoided.

Study Design Survey. Introduction App technology may provide a beneficial clinical resource for CHTs. Purpose of Study This descriptive study examined beneficial components for inclusion in a potential app for certified hand therapists to use as a clinical resource based on a nationwide survey. Methods Certified hand therapist members of the American Society of Hand Therapists were surveyed to evaluate preferences of content to be included in a potential clinical app. Results Most of the 341 respondents were Caucasian, female, 51-60 years old, with 21+ years' experience. Respondents preferred home program illustrations, video demonstrations, evidence-based resources, postoperative protocols, and functional outcome measures. Regarding app usage, 26.7% responded “definitely use the app” and 37.5% reported “highly likely to use the app” within a price range of $1-$20. Conclusion An ideal app should include home program media, evidence-based practice, postoperative protocols, and functional outcome measures related to reported diagnoses encountered in the clinic. Level of Evidence N/A.

Introduction Widespread over-prescription of proton pump inhibitors (PPIs) without an appropriate indication has financial and potentially adverse clinical consequences.

B cell precursor acute lymphoblastic leukemia (B-ALL) is the most common childhood malignancy. A subset of children with B-ALL are at high risk for relapse and death. Gene expression profiles in these high-risk B-ALLs is similar to that of Philadelphia chromosome positive ALL. Approximately half of these Ph-like B-ALL are characterized by genetic alterations that result in overexpression of CRLF2. CRLF2, together with the IL-7 receptor α chain, forms a receptor complex for the cytokine, TSLP. When TSLP binds, the receptor initiates downstream JAK2/STAT5 and PI3/AKT/mTOR pathway activation. The activating JAK mutations found in some CRLF2 B-ALL led to speculation that TSLP stimulation is not a factor in this disease. However, we find that TSLP increases phosphorylation of STAT5, AKT and S6 (downstream of mTOR) in CRLF2 B-ALL cells, including those with JAK defects. Activation of these pathways has been associated with oncogenesis and chemoresistance and their downstream targets include members of the Bcl2 family. The Bcl2 family pro-survival molecule Bcl-XL is a down stream target of STAT5 in Ph+ B-ALL. Mcl-1, another BCL2 family pro-survival molecule is known to be upregulated by mTOR activation via post-translational mechanisms in B cell lymphoma. We hypothesized that TSLP-induced JAK2/STAT5 and PI3/AKT/mTOR pathway activation contribute to chemoresistance in high risk CRLF2 B-ALL by upregulating the expression of Bcl-XL and Mcl-1. To test this hypothesis we cultured human CRLF2 B-ALL cell lines (MUTZ5 and CALL4) with and without TSLP and evaluated expression of the Bcl2 family pro-survival proteins, Bcl-XL, Mcl-1, and Bcl2. We found that TSLP induced significant increases in Bcl-XL and Mcl-1 proteins, but not Bcl2 in CRLF2 B-ALL cells. These cell lines have activating Jak mutations and thus reflect the ability of TSLP to increase expression of the Bcl2 family proteins in cases where activating JAK mutations are present. Next we evaluated the effect of Mcl-1 inhibitor on MUTZ5 and CALL4 cells. Preliminary data from these experiments show that cell counts in cultures treated with Mcl-1 inhibitor are reduce by >90% and this reduction is maintained in the presence of TSLP. These data provide evidence that TSLP-induced CRLF2 signals increase expression of Bcl2 pro-survival proteins, even in CRLF2 B-ALL cells with activating JAK mutations. These data also suggest that Mcl-1 inhibitors could be an effective treatment for this disease. Ongoing studies will evaluate the effect of TSLP and Mcl-1 inhibitors in primary CRLF2 B-ALL samples. Citation Format: Cornelia Stoian, Muhammad Omair Kamal, Olivia Francis, Rhaya Johnson, Simone Montgomery, Jacqueline Coats, Hannah Choi, Shania Aponte-Paris, Micheal Reed, Shanalee Martinez, Karina Mayagoitia, Evgeny Chirshev, Chunhua Song, Sinisa Dovat, Kimberly J. Payne. TSLP regulates expression of Bcl2 family proteins in Ph-like ALL with CRLF2 alterations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2444.

The role of TSLP in human B cell development is largely unknown and its function in context of IL7 is unstudied. We found that TSLP can replace IL7 in providing a signal essential for in vitro production and proliferation of human CD19+ Pax-5+ B cell progenitors. To study the role of TSLP in human B cell development, in the context of IL7 stimulation, we developed a novel xenograft model. Mouse IL7 is active on human cells, however, this is not the case for TSLP. We took advantage of this to develop a xenograft model system comprised of mice that provide human TSLP (+T mice) and control mice that do not (-T mice). Using this model we found that TSLP increases proliferation and upregulates Mcl-1 in CD34+CD19-IL7Ra progenitors resulting in a 3-4 fold expansion of the CD34+ pro-B cell compartment in +T as compared to -T mice. This expansion is maintained during subsequent stages of B cell development, partially due to increased protection from apoptosis that occurs independently of Bcl-2 family pro-survival proteins. While TSLP stimulates in vitro proliferation of pro-B cells, in vivo proliferation of B lineage precursors was similar in +T and -T mice suggesting redundancy with IL7. B cell subsets in normal pediatric bone marrow samples show progenitor ratios and Mcl-1 expression that mirrors that in +T xenograft mice. These data provide evidence that TSLP function in human B cell development includes both unique activities as well as activities redundant to those of IL7.

IL-7 is critical for mouse B cell development and available data suggest that TSLP has overlapping functions. Our previous in vitro studies show that IL-7 expands human B cell progenitors by ~60 fold (JI 2009 82:4255). Our recent experiments provide evidence that TSLP similarly expands human B cell progenitors in vitro and that primary human bone marrow stroma provides an in vivo source of both cytokines. To study interplay between IL-7 and TSLP in early stages of in vivo human B cell lymphopoiesis, we developed a novel xenograft model system that selectively provides IL-7 and/or TSLP stimulation. While mouse IL-7 can act on human cells, TSLP is species-specific. To overcome this obstacle we coupled a xenograft model system engineered to provide human TSLP (hTSLP) with IL-7 neutralizing antibodies. Preliminary data obtained using this model system transplanted with cord blood CD34+ cells shows that the production of B cell precursors is reduce by ~90% in mice that lack both IL-7 and hTSLP stimulation as compared to mice where both are present. The absence of hTSLP stimulation, alone, reduced B cell production by about 50%, while the effects due IL-7 neutralization, alone, were about half this. These data suggest that IL-7 and TSLP play an essential and at least partially overlapping role in human B cell development. Current studies are aimed at defining the differential stage-specific effects of TSLP and IL-7 on survival and proliferation of human B cell progenitors in vivo.

IL7 and TSLP are important in murine B cell development, however their role in human B lymphopoiesis is unclear. In contrast to other cytokines that act on B cell progenitors, TSLP lacks species cross reactivity and activates different intracellular signaling pathways in mice and humans. Thus, human models are essential for understanding the role of TSLP in human B lymphopoiesis. We developed a novel human-only model of in vitro B cell development that allows selective cytokine stimulation and used this model to show that IL-7 is essential for human B cell production where it increases B cell progenitors by over 60 fold (JI 2009 82:4255). Here we use this model and a novel xenograft model system to study human B lymphopoiesis from CD34+ HSCs in umbilical cord blood (CB). BrdU incorporation shows that TSLP induces proliferation of human B lineage cells to produce in vitro expansion of B cell progenitors similar to that observed for IL7. TSLP acts directly on human B cell precursors to induce STAT5 phosphorylation and upregulate PAX5. To evaluate the role of TSLP in vivo we developed a novel xenograft model system consisting of human TSLP+ (hTSLP+) and hTSLP- immune deficient NSG mice. Using the hTSLP+/- model system we show that hTSLP augments existing IL7 effects to expand human B lineage cells (from 37% to 68% total B lineage chimerism) in NSG mice, a strain that facilitates human B cell production. These data suggest that TSLP is important in human B lymphopoiesis.

Expression of the IL-7 receptor alpha (IL-7R) is a distinguishing feature of common lymphoid progenitors (CLP) in mice. Human B cell development has been thought to differ from that in mouse with respect to the requirement for IL-7. Our previous studies show that IL-7 plays a critical role in human B cell production (J Immunol. 2009, 182:4255). Here we use IL-7R expression to identify a human CLP population that can be generated from hematopoietic stem cells (HSCs) in umbilical cord blood (CB). Following two weeks of co-culture with primary human bone marrow (BM) stroma, CB CD34+ cells give rise to a CD34+CD19-IL-7R+ progenitor population that is absent from fresh, uncultured CB. IL-7R+ progenitors make up ~17% of the CD19-CD34+ cells present in culture at 2 weeks. A similar IL-7R+ human progenitor population is generated in the BM of immunodeficient mice following transplant with human CD34+ CB cells. FACS-sorted CD34+CD19-IL-7R+ progenitors produced in co-culture or in the human-mouse xenograft model give rise to CD19+ B cells and CD56+ NK cells in bulk and single cell culture, but lack myeloid potential in CFU assays and when transplanted into immunodeficient mice. Ongoing experiments will evaluate the T lineage potential of IL-7R+ progenitors in the human-mouse xenograft model. These data will be important for developing therapies to accelerate and enhance lymphoid reconstitution from HSCs in CB, a hematopoietic source used increasingly for stem cell transplant.