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Petra Bizikova

Assoc Professor

CVM Research Building 344


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Date: 05/01/22 - 8/31/23
Amount: $10,325.00
Funding Agencies: Morris Animal Foundation

Canine pemphigus foliaceus (PF) is one of the most common autoimmune skin diseases of the dog and is characterized by the autoantibody-mediated disassembly of epidermal adhesion complexes (i.e., desmosomes), a process known as “acantholysis”. Histologically, canine PF is defined by an intense infiltration of neutrophils into the epidermis which results in the development of intraepidermal pustules containing separated epidermal cells (i.e., acantholytic keratinocytes). Ultrastructural studies have suggested that neutrophils play a role in mediating acantholysis, however the mechanisms underlying their recruitment and activation in canine PF have been largely unexplored. The management of canine PF involves the long-term prescription of immunosuppressive drugs that result in treatment-limiting adverse events. Unfortunately, the development of safe, specific and targeted therapeutics for canine PF has been hindered by our limited understanding of the disease immunopathogenesis and is an unmet need in small animal clinical practice. Interestingly, the classical form of PF in humans is mediated by immunoglobulin G (IgG) autoantibodies and is a neutrophil-poor disease. Canine PF bears a stronger resemblance to “IgA pemphigus” of humans, which is a neutrophil-rich pustular disease mediated by immunoglobulin A (IgA) autoantibodies. Immunoglobulin A antibodies are well-known to recruit and activate neutrophils in human inflammatory and autoimmune diseases. We have previously identified IgA autoantibodies in the sera of approximately 20% of dogs with PF using indirect immunofluorescence. However, we believe that this is an underestimation due to the considerably higher serum titers of concurrent IgG autoantibodies in canine PF that likely outcompete IgA autoantibodies for binding to their mutual target.

Date: 07/01/21 - 6/30/23
Amount: $242,055.00
Funding Agencies: Nippon Zenyaku Kogyo Co., LTD. (ZENOAQ)

Study to Investigate Treatment for Canine Atopic Dermatitis in clinical cases in the dog. Patients from the North Carolina region will be recruited.

Date: 03/01/20 - 12/31/21
Amount: $13,132.00
Funding Agencies: American College of Veterinary Dermatology

Allergen-specific immunotherapy is known to exhibit slow onset of efficacy and, therefore, CSA or oclacitinib is often given concurrently during its initial phase. In some dogs, the length of this combined treatment can exceed a year. Allergen specific immunotherapy is so far the only treatment with the potential to modify the biology and course of disease by inducing an immune tolerance. Successful treatment requires induction of Treg, which, in turn, depend on: i) calcineurin-NFAT pathway, ii) IL2R-JAK/STAT pathway and iii) TGF-beta-Smad pathway. Disruption of NFAT, JAK1 or JAK3 signaling was shown to diminish differentiation of Treg. Both CSA and oclacitinib exert a direct effect on NFAT signaling, IL-2 production and/or IL-2 signaling via JAK1/JAK3-STAT pathway. In dogs, the effect of CSA on Treg in vivo is limited to short-term studies. No in vivo information is available for oclacitinib and the effect of a long-term use of CSA and oclacitinib on Treg in dogs remains unanswered. Indeed, if CSA or oclacitinib were to negatively affect the development or function of Treg, then they could negatively affect the development and expansion of Treg, and thus the outcome of ASIT. Such information would be important for clinicians, who frequently prescribe these drugs together with ASIT. Therefore, the goal of this study is to evaluate the effect of a long-term use of CSA and oclacitinib on Treg numbers and regulatory cytokine levels in dogs affected with AD. Blood from 15 client-owned dogs with AD receiving CSA or oclacitinib at dosages approved for AD treatment for ≥9 months will be evaluated for the percentage of CD4+CD25highFOXP3+ using flow cytometry. Blood from 15 healthy dogs, 15 dogs with untreated AD and 15 dogs well-controlled with ASIT exclusively will serve for comparison. Regulatory cytokines (IL-10 and TGF-beta) will be measured in the serum by ELISA. Specific Aim #1: to determine percentage of CD4+CD25highFOXP3+ Treg cells in dogs with AD controlled with CSA or oclacitinib or ASIT and in healthy dogs and dogs with uncontrolled AD Specific Aim #2: to measure serum IL-10 and TGF-beta concentrations in dogs with AD controlled with CSA or oclacitinib or ASIT and in healthy dogs and dogs with uncontrolled AD

Date: 03/01/17 - 8/31/18
Amount: $22,458.00
Funding Agencies: Royal Canin R & D

Cutaneous adverse food reactions (CAFR) are frequent in dogs. The diagnosis of CAFR is currently based on a long-lasting (6-8 weeks) elimination diet (ED) trial. The duration of ED remains controversial. Although the persistence of food allergens in the body in quantities sufficient to elicit reactions for up to three months is difficult to explain immunologically, it is believed that the chronicity of skin changes and self-perpetuating cutaneous inflammation seen in some dogs with chronic disease is the main rationale for this lengthy ED. This lengthy ED presents a challenge from the prospective of client compliance. Unfortunately, there is no other reliable test (e.g. IgE serology, intradermal or skin prick test) to assist clinicians in the diagnostic process of canine CAFR. We believe that the current procedures for the diagnosis of CAFR should be in depth revisited and that every effort should be made to 1) reduce the length of ED 2) reevaluate the in vitro as well as skin tests performance. To reduce the ED duration, we propose to use glucocorticoids in the initial phase to “deactivate” the ongoing inflammation and thus shorten the time to “return to normal status” before challenges. This concurrent use of glucocorticoids in the first phase of ED forms the basis of the short (three to five weeks) restriction-provocation protocol proposed in this study. Responses to food challenges at the end of ED will be compared with the results of IgE serology and prick test to evaluate the sensitivity and specificity of these tests.

Date: 03/01/17 - 2/01/18
Amount: $14,000.00
Funding Agencies: American College of Veterinary Dermatology

Pemphigus foliaceus (PF) is the most common autoimmune pustular skin disease of dogs. The current diagnostic approach is based on the combination of clinical and microscopic findings and exclusion of clinically and histologically resembling diseases such as superficial pyoderma (SP) or, more rarely, pustular dermatophytosis. Indeed, exclusion of pyoderma is often difficult and critically important, especially in dogs without the classic facial lesion distribution commonly associated with PF. In such cases, caution is warranted in relying on keratinocyte acantholysis alone for the diagnosis of PF due to its lack of specificity, and a response to empirical treatment and/or bacterial/fungal culture are required to rule out resembling diseases prior to the immunosuppression. This process takes considerable time during which PF may worsen significantly and, therefore, a more rapid and sensitive test on which a clinician could rely would be of a great value. Our previous study demonstrated that 81% of dogs with the classic facial lesions (pustules, erosions and crusts on the nasal planum/dorsal nose with or without other lesion distribution) had circulating anti-desmocollin 1 (anti-DSC1) IgG, while none of the thirty-five healthy dog sera tested positive (positive likelihood ration >2; negative likelihood ration <0.5). The sensitivity of this assay in dogs with PF without the classic facial phenotype remains unknown. The same study reported that none of the eight dogs with SP produced detectable levels of anti-DSC1 IgG. The number of tested dogs was too low to accurately calculate the specificity of this test to distinguish PF from SP. The goal of this study is to validate the sensitivity and specificity of the anti-DSC1 IgG assay for diagnosis of PF and its ability to differentiate PF from SP. Sera from dogs with a confirmed diagnosis of PF independently of the disease phenotype, from dogs with SP and control dogs will be tested for the presence of circulating anti-DSC1 IgG antibodies on a previously described assay using canine DSC1-transfected cells. The sensitivity and specificity of the anti-DSC1 IgG assay for diagnosis of PF will be calculated using standard formulas (see material and methods). Additionally, the specificity of the assay for distinguishing PF from SP will be calculated as the number of dogs with SP without detectable anti-DSC1 IgG divided by the total number of dogs with SP. The obtained values will be used further to calculate the likelihood ratios. Such a test, if proven to be sufficiently sensitive for canine PF and able to reliably distinguish PF from SP, could be used broadly to assist veterinarians and dermatologists in the diagnosis of canine PF.

Date: 10/01/16 - 9/30/17
Amount: $42,333.00
Funding Agencies: Alphanosos

We take 9 dogs which are currently available and we treat in a cross over scenario: We wanted to start with preventive setting: 4 dogs receive placebo topically starting at days -3 (before challenge with bacterial slurry), 5 dogs receive your drug topically starting at days -3 topically. Then we challenge with 107 (left side) and 109 (right side) and we observe development of lesion 24, 48 and 72 h after bacterial challenge. We also can observe for remission of lesions (“we” means together with a board certified dermatologist). After wash out time (30 days) we treat again now the other 4 dogs with your drug and the former "drug" dogs with placebo, again a wash out period which might be even longer as we have to make sure, the dogs are absolutely "clean" when leaving the study

Date: 06/01/15 - 3/31/17
Amount: $91,239.00
Funding Agencies: Ark Animal Therapeutics

Pyoderma in dogs is a frequent problem veterinarians must deal with on a daily basis and is troublesome to owners of dogs that require repeated treatments. Because of the ever-increasing antibiotic resistance, pyoderma is a growing a treatment challenge risk. To investigate new treatment strategies, especially strategies targeting specifically Staphylococcus pseudintermedius, it would be helpful to have access to a canine model of pyoderma that would represent the natural disease as closely as possible. Since there is no established model, there is a need to establish a dog model of pyoderma. In the present case, this dog model of pyoderma is intended to be established to test a new vaccine strategy against St. pseudintermedius. Regrettably, all previously published models of pyoderma in rodents were the result of an intradermal injection of bacteria (Shraer et al., 1977), which resulted in a lesion clinically and histologically incompatible with the typical superficial pyoderma. Therefore, there is a need to establish a model of canine superficial pyoderma; a model that would clinically and histologically resemble that of the natural disease. Once this dog model is established, it can be used for investigation of new strategies for prevention and treatment of pyoderma.

Date: 09/23/13 - 7/31/16
Amount: $28,599.00
Funding Agencies: Royal Canin R & D

Cutaneous adverse food reactions (CAFR) in dogs are common cause of non-seasonal itch with or without accompanying skin lesions. The aid for diagnosis or treatment of CAFR is a feeding of the affected dogs with a novel protein diet or, recently, with a diet composed of hydrolysed proteins. Studies in people established that only highly hydrolysed diets with peptides smaller than 3000 DA might be considered hypoallergenic. Interestingly, up to 50% of dogs with CAFR enrolled in three controlled studies exhibited increases in clinical signs after ingesting partial hydrolysates derived from foods to which they were hypersensitive. Anallergenic is composed of highly hydrolysed feather protein. The goal of this double-blinded, cross-over study is to determine the clinical allergenicity of Anallergenic in dogs with proven chicken-induced cutaneous adverse food reactions. The results will be compared to the allergenicity of another hydrolyzed chicken diet (Hill’s z/d Ultra dry) in the same population of dogs.

Date: 06/01/13 - 12/31/14
Amount: $37,825.00
Funding Agencies: Nexvet Biopharma Pty Ltd.

Atopic dermatitis is a common chronic allergic skin disease of humans and dogs. Among the molecules known to be present in the skin of dogs with atopic dermatitis is the cytokine Tumor Necrosis Factor (TNF)-alpha, an upstream mediator that triggers a wide array of secondary inflammatory reactions. The goal of this study is to inject client-owned dogs with natural atopic dermatitis with a dog monoclonal antibody that blocks TNF-alpha, hoping to prevent inflammatory events leading to skin lesions and itch.

Date: 11/01/12 - 10/31/14
Amount: $28,216.00
Funding Agencies: Nexvet Biopharma Pty Ltd.

Neural Growth Factor (NGF) is a mediator that is responsible for the growth of nerve endings, and recent data suggest that this cytokine might be involved in promoting itch. This study is a proof-of-concept trial that aims at determining if injecting a recombinant dog antibody that inactivates dog NGF has any efficacy in reducing the recurrence of itch after steroid administration in dogs with the common allergic skin disease atopic dermatitis.

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