Keep the cat, change the care pathway: A transformational approach to managing Fel d 1, the major cat allergen.

BACKGROUND: Allergies to cats are the most common animal-origin allergy, and affect approximately 1 in 5 adults worldwide. The prevalence of allergy to furry animals has been increasing, and allergy to cats is a major risk factor for the development of asthma and rhinitis. The diagnosis of cat allergy is now well established. The exact significance of component-resolved diagnosis in the diagnosis of cat allergy remains to be fully understood. Allergen avoidance is effective but often has a psychologic impact. Allergen immunotherapy is not well demonstrated. There is a need for innovative approaches to better manage cat allergens. Next-generation care pathways for asthma and rhinitis will define the place of cat allergen avoidance. METHODS AND RESULTS: This manuscript, based on content presented at the European Academy of Allergy and Clinical Immunology Congress 2019, provides information on the prevalence and impact of cat allergies and the molecular biology of Fel d 1, the major cat allergen. DISCUSSION: The authors present the scientific basis of a novel care pathway that utilizes anti-Fel d 1 IgY antibodies to safely and effectively neutralize Fel d 1 after its production by the cat but before human exposure. CONCLUSION: Efficacy of a feline diet with an egg product ingredient containing anti-Fel d 1 IgY antibodies was demonstrated in vitro, ex vivo, and in vivo, and further validated by a pilot exposure study involving cat-allergic human participants.

Supplementation of diets with bovine colostrum influences immune function in dogs.

While the need for colostrum in neonates is well established, the systemic effect of feeding bovine colostrum (BC) to adult humans is gaining increasing attention. However, no systematic studies evaluating the immunomodulatory effect of BC in dogs have been reported. The aim of the present study was to evaluate the immunomodulatory effect of dietary supplementation of BC in dogs. The study was conducted in two phases: pre-test (8 weeks) and test (40 weeks), with twenty-four dogs (mean age 2.5 years) randomised into two groups. In the 'pre-test' phase, both groups were fed a nutritionally complete diet. At the end of the 'pre-test' phase, all dogs received a canine distemper virus (CDV) vaccine, and dogs in the 'test group' were switched to a diet supplemented with 0.1% spray-dried BC. Response to the CDV vaccine was evaluated by measuring vaccine-specific plasma IgG levels. Gut-associated lymphoid tissue response was assessed by measuring faecal IgA levels. Gut microbiota were evaluated by the temporal temperature gel electrophoresis methodology. Dogs fed the BC-supplemented diet demonstrated a significantly higher vaccine response and higher levels of faecal IgA when compared with the control group. Supplementing diets with BC also resulted in significantly increased gut microbiota diversity and stability in the test group. In conclusion, diets supplemented with BC significantly influence immune response in dogs.

Fel d1 Blocking Antibodies: A Novel Method to Reduce IgE-Mediated Allergy to Cats.

Fel d1 is an important allergen produced by cats that causes IgE reactions in up to 95% of cat-allergic adults. Immunotherapy to reduce human allergy to cats has demonstrated that people have the capacity to produce allergen-specific neutralizing antibodies that block IgE-mediated allergic responses. We wished to determine if "blocking" antibodies could be used to reduce the IgE binding ability of cat allergens prior to their exposure to humans. Here, we describe the characterization of Fel d1-specific antibodies. We demonstrated the efficacy of a rabbit polyclonal and an allergen-specific chicken IgY to bind to Fel d1 in cat saliva and block Fel d1-IgE binding and IgE-mediated basophil degranulation. Fel d1 blocking antibodies offer a new and exciting approach to the neutralization of cat allergens.

Supplementation of Diets With Spirulina Influences Immune and Gut Function in Dogs.

Spirulina refers to two species of blue green algae (Arthrospira platensis, and A. maxima) consumed by humans as food for centuries. While, Spirulina has been shown to have immune enhancing properties in several animal and human studies, there are no systematic studies in dogs. The aim of this study was to evaluate the immunomodulatory effect of dietary supplementation with Spirulina in dogs. The study was conducted in two phases: Pre-test (8 wks.) and Test (42 wks.). Thirty adult dogs (mean 2.9 yrs.) were randomized into two groups and fed a nutritionally complete diet in the "Pre-test" phase. At the end of "Pre-test" phase all dogs received a rabies vaccine, and dogs in "test group" were switched to diet supplemented with dried Arthrospira platensis (Spirulina). Response to rabies vaccine was evaluated by Rapid Fluorescent Focus Inhibition Test (RFFIT). Gut immune response was assessed by measuring fecal IgA. Gut microbiota was evaluated by Temporal Temperature Gel Electrophoresis (TTGE) methodology. Repeated measures ANOVA was used to test for differences between groups and statistical significance considered to be p < 0.05. Dogs fed diets supplemented with Spirulina demonstrated enhanced immune status by showing significantly higher vaccine response and higher levels of fecal IgA as compared to the control group. Supplementing diets with Spirulina also resulted in significantly increased gut microbiota stability in the test group. In conclusion, diets supplemented with Spirulina significantly enhanced immune response and gut health in dogs.

Supplementation of Diets With Bovine Colostrum Influences Immune and Gut Function in Kittens.

In its early life a kitten faces many significant events including separation from its mother, re-homing and vaccination. The kitten is also slowly adapting to their post-weaning diet. Recent advances in companion animal nutrition have indicated that functional ingredients such as colostrum can help support the immune system and gastrointestinal health. Here we report for the first time the effect of feeding a diet containing 0.1% spray dried bovine colostrum (BC) to growing kittens on gut-associated lymphoid (GALT) tissue responses, systemic immune responses, and on intestinal microbiota stability. BC supplementation induced increased faecal IgA expression, and a faster and stronger antibody response to a rabies vaccine booster, indicative of better localised and systemic immune function, respectively. BC supplementation also helped to maintain kittens' intestinal microbiota stability in the face of a mildly challenging life event. These results show that BC supplementation can help strengthen the immune system and enhance the gut microbiota stability of growing kittens.

Pilot study to evaluate the effect of oral supplementation of Enterococcus faecium SF68 on cats with latent feline herpesvirus 1.

Feline herpesvirus 1 (FHV-1) infection is extremely common in cats and is frequently associated with morbidity because of recurrent ocular and respiratory clinical signs of disease. Enterococcus faecium strain SF68 is an immune-enhancing probiotic used as a dietary supplement. In this pilot study, 12 cats with chronic FHV-1 infection were administered either SF68 or a placebo, monitored for clinical signs of disease, monitored for FHV-1 shedding, and evaluated for FHV-1 specific humoral and cell-mediated immune responses and fecal microbiome stability. Fecal microbial diversity was maintained throughout the study in cats supplemented with SF68, but decreased in cats fed the placebo, indicating a more stable microbiome in cats fed SF68. While clinical results varied among individual cats, the overall findings suggest that administration of the probiotic lessened morbidity associated with chronic FHV-1 infection in some cats. Additional study is warranted to determine efficacy in a clinical setting.

Influence of time and phenotype on salivary Fel d1 in domestic shorthair cats.

OBJECTIVES: Fel d1 is a major allergen that may affect humans sensitive to cat allergens, and it can be detected in the saliva and on the hair of cats. We studied the variability of salivary Fel d1 in typical house cats (ie, neutered domestic shorthair cats) and the factors that could be associated with that variability. METHODS: Saliva samples were collected from 64 cats, twice daily, every other day, for a year, at two locations (Missouri, USA, and Ontario, Canada). Salivary Fel d1 levels were measured using an immunoassay. Correlations and linear mixed-effects model analyses were run to assess which factors significantly affected the Fel d1 levels. RESULTS: Salivary Fel d1 levels varied significantly both within and among cats. Cat averages over the year ranged from 0.4-35 µg/ml, and a higher average correlated with a higher SD (P <0.001). The first collection of the day tended to be higher than the afternoon collection (P <0.001). Sex, coat color or body size did not relate to cats' average Fel d1 production, but older cats tended to have lower salivary Fel d1 levels (P <0.001). Fel d1 levels from four samples were reliable in identifying cats producing stable low levels of Fel d1. CONCLUSIONS AND RELEVANCE: We observed a wide and continuous range of salivary Fel d1 production in domestic shorthair cats. In particular, a subset of cats had stable low levels throughout the course of the year, and they can be identified by analyzing a few saliva samples rather than their physical appearance.

Reduction of active Fel d1 from cats using an antiFel d1 egg IgY antibody.

BACKGROUND: Fel d1 is the most important allergen from cats. Fel d1 is produced primarily in saliva and spread to the haircoat during grooming and then transferred to the environment via hair and dander. OBJECTIVES: A novel approach to reducing allergenic Fel d1 exposure was evaluated, involving binding the Fel d1 with an anti-Fel d1 polyclonal egg IgY antibody. The hypothesis was that hair from cats who had been fed foods containing anti-Fel d1 IgY would show a significant reduction in active Fel d1 (aFel d1). METHODS: Hair collected from 105 cats completing a 12-week study was evaluated for aFel d1 via ELISA. Hair was collected four times over a 2-week baseline period, then weekly during the 10 week treatment period during which cats consumed a food containing the anti-Fel d1 IgY. RESULTS: Baseline aFel d1 (µg/g hair) varied greatly among the cats in this study. From week 3, there was a significant reduction in mean aFel d1 with an overall average decrease of 47% by week 10, ranging from a 33-71% decrease vs baseline. Cats with the highest baseline aFel d1 showed the greatest decrease in aFel d1. CONCLUSIONS & CLINICAL IMPLICATIONS: Feeding anti-Fel d1 IgY to cats successfully reduced aFel d1 on their haircoat with the greatest decreases observed in cats with initially high levels. Feeding a diet with anti Fel d1 IgY significantly reduced the active Fel d1 on the hair of cats.

Anti-Fel d1 immunoglobulin Y antibody-containing egg ingredient lowers allergen levels in cat saliva.

OBJECTIVES: Fel d1 is the major cat allergen, causing IgE reactions in up to 90% of cat-allergic adults. Fel d1 secreted in saliva is spread to the haircoat during grooming. Current management includes attempts to reduce or eliminate exposure to Fel d1. A novel approach to reducing immunologically active Fel d1 (aFel d1) exposure, which involves binding the Fel d1 with an anti-Fel d1-specific polyclonal egg IgY antibody (sIgY), was evaluated. The hypothesis was that saliva from cats fed diets containing this sIgY would show a significant reduction in aFel d1. METHODS: Two trials in cats were completed. In trial 1, saliva was collected 0, 1, 3 and 5 h post-feeding during a 2 week baseline and subsequent 6 week treatment period. Trial 2 included a control and treatment group, and saliva was collected once daily. Trial 2 cats were fed the control diet during a 1 week baseline period, and then fed either control or sIgY diet during the 4 week treatment period. Fel d1-specific ELISA was used to measure salivary aFel d1. Data were analysed using repeated-measures ANOVA and a linear mixed-model analysis. RESULTS: Salivary aFel d1 decreased post-treatment in both trials. There were no differences in aFel d1 based on time of collection relative to feeding in trial 1. In trial 2, 82% of treatment group cats showed a decrease in aFel d1 of at least 20% from baseline vs just 38% of control cats. Only one (9%) treatment cat showed an increase in aFel d1 vs 63% of control cats. CONCLUSIONS AND RELEVANCE: Feeding sIgY significantly reduced aFel d1 in the saliva of cats within 3 weeks. Although additional research is needed, these findings show promise for an alternative approach to the management of allergies to cats.

The aging feline kidney: a model mortality antagonist?

Traditional thinking views apparently non-programmed disruptions of aging, which medical science calls geriatric diseases, as separate from 'less harmful' morphological and physiological aging phenotypes that are more universally expected with passage of time (loss of skin elasticity, graying of hair coat, weight gain, increased sleep time, behavioral changes, etc). Late-life disease phenotypes, especially those involving chronic processes, frequently are complex and very energy-expensive. A non-programmed process of homeostatic disruption leading into a death trajectory seems inconsistent with energy intensive processes. That is, evolutionary mechanisms do not favor complex and prolonged energy investment in death. Taking a different view, the naturally occurring feline (Felis silvestris catus) renal model suggests that at least some diseases of late life represent only the point of failure in essentially survival-driven adaptive processes. In the feline renal model, individuals that succumbed to failure most frequently displayed progressive tubular deletion and peritubular interstitial fibrosis, but had longer mean life span than cats that died from other causes. Additionally, among cats that died from non-renal causes, those that had degrees of renal tubular deletion and peritubular interstitial fibrosis also had longer mean life span than those cats with no changes, even though causes of death differed minimally between these latter two groups. The data indicate that selective tubular deletion very frequently begins early in adult life, without a clear initiating phase or event. The observations support a hypothesis that this prolonged process may be intrinsic and protective prior to an ultimate point of failure. Moreover, given the genetic complexity and the interplay with associated risk factors, existing data also do not support the ideas that these changes are simple compensatory responses and that breed- or strain-based 'default' diseases are inevitable results of increasing individual longevity. Emerging molecular technology offers the future potential to further evaluate and refine these observations. At present, the existence of plastic and adaptive aging programming is suggested by these findings.

Immunoglobulins in dogs: correspondence and maturation in 15 litters of German shepherd dogs and their dams.

Some dog breeds, including the German shepherd dog (GSD), are predisposed to immune-related disorders. The authors prospectively described development of serum and faecal IgA and serum IgE in GSD from puppies until adulthood and the relationship between mothers and their offspring. Further, the authors tested whether dogs with lower serum IgA also have low faecal IgA and/or serum IgE. To reveal whether any of the parameters could be proven to influence the immune response, the authors also measured serum IgG against canine distemper virus (CDV). To test their hypothesis, the authors used linear mixed models to investigate the relationship of serum IgA, serum IgE and faecal IgA levels in litters and their mothers. Fifteen GSD bitches beginning at 42 days of pregnancy and subsequently all of their offspring (n=83 puppies), reared under well-controlled conditions, were included. All dogs came from the kennel of the Swedish Armed Forces. Serum IgE, serum IgA and faecal IgA levels were lower in seven-week-old puppies than at one year of age. There was no relationship in Ig concentrations between bitches and their puppies at seven weeks of age. Dogs with higher faecal IgA had higher IgG titres against CDV, indicating a favourable systemic immune status.

The impact of weight loss on circulating cytokines in Beagle dogs.

Chronic low-grade inflammation in obesity is characterized by an increased production of pro-inflammatory and chemotactic cytokines that are contributing to insulin resistance and related co-morbidities. Cytokines act in networks and exhibit pleiotropic effects so we investigated the circulating levels of a wide array of cytokines (pro and anti-inflammatory, chemotactic and growth factors) in a canine model of weight loss. The dogs served as their own control in order to study the impact of weight loss independent of potential confounding factors, such as history of excess weight or gender. While low-grade inflammation had been previously investigated in obese dogs by measuring changes in adipokines, acute phase proteins and key pro-inflammatory cytokines, to the best of our knowledge this is the first study to evaluate how weight loss impacts a wide array of circulating cytokines. Eighteen overweight Beagle dogs were recruited (six spayed females and 12 neutered males), and none of them were grossly obese according to the body condition score (BCS). All the dogs reached an ideal weight by the end of the program. Parameters were assessed before (baseline), at mid-point (month 3) and at end-point (month 6). Plasma GM-CSF, IL-2, Il-4, IL-6, IL-7, IL-8, IL-10, IL-15, IL-18, IFNγ, IP-10, TNFα, monocyte chemotactic protein 1 (MCP-1), keratinocyte chemokine (KC) were measured with canine multiplex immunoassays. Fat mass was assessed by dual energy X-ray absorption (DEXA). Several cytokines decreased throughout the weight loss program (p<0.01) and were correlated with the percentage of fat measured by DEXA (p<0.05): chemotactic (MCP-1), growth factors (GM-CSF, IL-7 and IL-2), and pro-inflammatory (KC and IL-18). We could not show trends for several cytokines, possibly because their level may be lower than the assay sensitivity: anti-inflammatory (IL-4 and IL-10), and pro-inflammatory (IL-6 and TNFα). In conclusion, while our findings for several pro-inflammatory and chemotactic cytokines are in accordance with human and rodent studies, we may have identified additional cytokines, such as growth factors, related to obesity-induced low-grade inflammation. Considering the weight loss was enabled by an adjusted diet, the role of this association of cytokines in insulin resistance and related co-morbidities needs to be clarified. Our results could help better understand the cytokine biology in dogs, and as such are relevant for further elucidating the relationship between immune function and metabolism/nutrition.

Milk oligosaccharides over time of lactation from different dog breeds.

The partnership of humans and dogs goes back to over 10'000 years, yet relatively little is known about a dog's first extra-uterine nutrition particularly when it comes to milk oligosaccharides. We set out to identify and quantify milk oligosaccharides over the course of lactation from different dog breeds (Labrador retriever, Schnauzer and 3 Alaskan husky crossbreeds). To this end, 2 different chromatographic methods with fluorescence and mass spectrometry detection were developed and one was validated for quantification. Besides lactose and lactose-sulphate, we identified 2 different trisaccharides composed of 3 hexose units, 3'sialyllactose (3'SL), 6'sialyllactose (6'SL), 2'fucosyllactose (2'FL), and a tetrasaccharide composed of 2 hexoses, an N-acetylhexosamine and a deoxyhexose. 3'SL was present at the highest levels in milk of all dog breeds starting at around 7.5 g/L and dropping to about 1.5 g/L in the first 10 days of lactation. 6'SL was about 10 times less abundant and 2'FL and the tetrasaccharide had rather varying levels in the milk of the different breeds with the tetrasaccharide only detectable in the Alaskan husky crossbreeds. The longitudinal and quantitative data of milk oligosaccharides from different dog breeds are an important basis to further our understanding on their specific biological roles and also on the specific nutritional requirements of lactating puppies.

Evaluation of cytokines and hormones in dogs before and after treatment of diabetic ketoacidosis and in uncomplicated diabetes mellitus.

In human beings, diabetes mellitus (DM) and diabetic ketoacidosis (DKA) are recognized as proinflammatory states and dysregulation of cytokines has been linked to some potentially fatal complications. Cytokine profiles of dogs with DM or DKA have not been reported. The objectives of this study were to compare cytokine and hormone concentrations in dogs with DKA before and after resolution of ketoacidosis, to compare these concentrations before treatment of DKA to those measured in dogs with uncomplicated DM and healthy dogs, and to compare concentrations in dogs with uncomplicated DM to those measured in healthy dogs. 27 dogs were included in this prospective clinical study. 18 dogs had naturally-occurring disease (9 DKA and 9 DM) and 9 dogs were healthy. Serum GMCSF, IL-2, IL-4, IL-6, IL-7, CXCL8, IL-10, IL-15, IL-18, IFNγ, IP-10, TNFα, Monocyte Chemoattractant Protein-1 (MCP-1), Keratinocyte Chemoattractant (KC), glucagon, leptin, adiponectin, and resistin were assayed using Milliplex MAP Canine kits.(2)(,)(3) IL-18, resistin, and GMCSF concentrations were significantly higher in dogs with DKA before treatment compared to after resolution of ketoacidosis. CXCL8, MCP-1, KC, and resistin were significantly higher in DKA dogs compared to healthy controls, and KC was also significantly higher in DKA compared to DM dogs. Additionally, CXCL8 and MCP-1 were significantly higher in dogs with DM compared to healthy controls. Significant differences were not detected in concentrations of the other measured analytes, including glucagon. It is concluded that IL-18, resistin, GMCSF, and KC may be involved in the pathogenesis of canine DKA, and their importance in this pathogenesis may be as great as that of glucagon. Dysregulation of CXCL8 and MCP-1 may be involved in the pathogenesis of DM in dogs.

Emerging paradigms in immunonutrition.

Nutritional immunology is the study of the relationship between food and the immune system. It evolved with the study of immune deficiencies caused by malnutrition. However, because of technological advances made over the past few decades, malnutrition is no longer the main cause of lowered immune status in otherwise healthy people/animals. Rather, life stage (neonate or old age) and natural stressors have taken over as the primary cause for immune deficiency. Unlike malnutrition, immune deficiency due to life stage or natural stress cannot be addressed by correcting underlying nutritional problems. Lowered immune status because of life stage or naturally occurring stress is characterized by reduced capacity to process and present foreign antigens to immune cells, resulting in a less efficient or altered immune response that leads to increased susceptibility to infections and an increase in autoimmunity and cancers. Beyond providing essential nutrients, diet can actively influence the immune system. Over 65% of the immune cells in the body are present in the gut, making the gut the "largest immune organ." Receptors present on the immune cells in the gut are the primary targets for immunomodulation via diet. Diet interacts with the immune system at multiple levels, starting with providing basic nutrients, then moving on to providing higher levels of key nutrients such as protein, vitamins, and minerals, and leading to a more focused modulation of the immune system. A framework outlining this interaction, along with relevant examples, will be discussed.

A single IGF1 allele is a major determinant of small size in dogs.

The domestic dog exhibits greater diversity in body size than any other terrestrial vertebrate. We used a strategy that exploits the breed structure of dogs to investigate the genetic basis of size. First, through a genome-wide scan, we identified a major quantitative trait locus (QTL) on chromosome 15 influencing size variation within a single breed. Second, we examined genetic variation in the 15-megabase interval surrounding the QTL in small and giant breeds and found marked evidence for a selective sweep spanning a single gene (IGF1), encoding insulin-like growth factor 1. A single IGF1 single-nucleotide polymorphism haplotype is common to all small breeds and nearly absent from giant breeds, suggesting that the same causal sequence variant is a major contributor to body size in all small dogs.

Protein microarray analysis of disease activity in pediatric inflammatory bowel disease demonstrates elevated serum PLGF, IL-7, TGF-beta1, and IL-12p40 levels in Crohn's disease and ulcerative colitis patients in remission versus active disease.

OBJECTIVES: Cytokines and growth factors play a major role in the dysregulated immune response in inflammatory bowel disease (IBD). We hypothesized that significant differences exist between the serum cytokine and growth factor profiles of pediatric IBD patients with active disease (AD) and those in remission, and that levels of some of these soluble mediators may be used to define regulators in IBD and determine disease activity. METHODS: Eighty-eight consecutive patients with confirmed Crohn's disease (CD) and ulcerative colitis (UC) seen at the Duke Children's Hospital were prospectively enrolled and a serum sample was obtained. Data were recorded at the time of serum collection to calculate disease activity indices. The relative expression of 78 cytokines, growth factors, and soluble receptors was determined using proprietary antibody-based protein microarrays amplified by rolling circle amplification. SPSS 8 (SPSS Inc., Chicago, IL) was used to compare protein profiles for CD and UC patients in clinical remission (CR) versus AD. RESULTS: Sixty-five CD patients and 23 UC patients were enrolled. Forty-one CD patients had available samples and PCDAI results. Twenty-two patients were in remission PCDAI < or = 12.5 (median 5), 19 patients had disease activity >15 (median 30). Univariate analysis revealed that PLGF, IL-7, IL-12p40, and TGF-beta1 cytokine levels were significantly elevated for patients in CR versus AD (p < 0.01). Twelve UC serum samples had Seo/Truelove Witt AI for analysis. Five patients were in remission by TW AI and Seo AI < or =110 and 7 patients had active mild-to-severe disease by TW and Seo AI >110. Only one cytokine, IL12p40, showed significance between CR versus AD (p < 0.02). CONCLUSIONS: Surprisingly, we found no differences in circulating levels of proinflammatory cytokines but found that pediatric IBD patients in remission compared to those with AD had higher levels of specific circulating cytokines, including the regulatory cytokines IL-12p40 and TGF-beta1. It may be that these cytokines directly regulate intestinal inflammation in IBD or reflect the activity of T regulatory cells in negatively regulating the inflammatory response. Further studies will be needed to validate our results to define the molecular pathways involved in the intestinal immune response in man.

Cerebral palsy is characterized by protein mediators in cord serum.

Cerebral palsy (CP) is a major neurodevelopmental disability in childhood. An association between intrauterine infection and CP has been reported. We examined the relationship between inflammatory mediators in cord serum and CP in term and preterm children. Regional multicenter study was conducted on 19 CP children and 19 gestation-matched paired controls. CP children (n = 27) were further compared with controls of similar gestation at birth (n = 25). Serum levels of 78 protein mediators were analyzed. Eleven analytes correlated with the length of gestation both in cases and controls. In paired analysis, B-lymphocyte chemoattractant, ciliary neurotrophic factor, epidermal growth factor, interleukin (IL)-5, IL-12, IL-13, IL-15, macrophage migration inhibitory factor, monocyte chemoattractant protein-3, monokine induced by interferon gamma, and tumor necrosis factor-related apoptosis-inducing ligand were higher in children with CP (p < or = 0.05). Preterm infants with CP showed higher epidermal growth factor and lower levels of granulocyte-macrophage colony-stimulating factor, IL-2, macrophage-derived chemokine, and pulmonary and activation-regulated chemokine than their paired controls. Inflammatory mediators and growth factors serve as a footprint of the fetal response to an insult manifesting after birth as a permanent brain damage. The cytokine patterns at birth differ between premature and term infants who develop CP.