By Elizabeth Davis, DVM
What is immunomodulation? By definition this simply means that we modify the natural immune response. This can occur in one of two ways, either by boosting the response with immunostimulants or suppressing the response with medications like corticosteroids. Currently immunostimulation has become a more widely discussed method of managing horses suffering from infectious disease.
An ideal situation when a host is exposed to pathogen challenge (e.g. bacteria or virus) is to have optimal immunity that protects the host from disease. However, if we have a situation of overwhelming challenge or an inadequate immune response then we have an individual that succumbs to infectious disease. In many cases specific therapy in the form of antibacterial, antiprotozoal, antiparasitic or antifungal therapy will work in combination with the immune system to aid with pathogen clearance. In some instances though, the addition of an immunostimulant will aid in “boosting” the immune response so that we have a more robust immune response acting in coordination with the antimicrobial drug to clear the infection. Some examples of instances where immunostimulant therapy have been shown to be of benefit to equine patients include prevention of disease prior to stress such as long distance transport or weaning, bacterial respiratory disease, endometritis (infection of the lining of the uterus) or improvement of nasal secretions associated with viral respiratory disease (Equine Herpes Virus, EHV). When a person is asking whether this type of treatment is right for their horse, it is important to consult with a veterinary professional to determine the appropriateness of such therapy.
Specific examples of diseases
Respiratory infection (prophylaxis and treatment)
Immunostimulants may be beneficial for treatment of chronic, infectious pulmonary disease in young horses. An example would be a horse that has experienced clinical disease for several weeks with incomplete resolution following antibacterial therapy. The indications for immunostimulant therapy in horses are relatively specific for the management of infectious disease. The mechanism of action of nonspecific immunostimulation is activation of specific white blood cells that produce proteins of inflammation called cytokines. Immunostimulant therapy may not be effective in patients with acute, fulminate infections because the immune response is likely maximally stimulated by the infectious agent. Therefore, these agents are useful as a preventative therapy or for chronic respiratory infection that is incompletely resolved. Horses with primary immunodeficiency syndromes, such as severe combined immunodeficiency syndrome of Arabian foals, are incapable of responding to immunostimulant therapy. Immunostimulant therapy is indicated in horses with chronic bacterial or viral respiratory infections due to immunosuppression or immunotolerance to the organism. Prophylactic administration of immunostimulant preparations prior to stressful events such as weaning or long-distance transportation may decrease onset of infectious disease that is associated with reduced immune responses and stress.
In equine medicine, Propionibacterium acnes (EqStimÒ, Neogen Inc.) is recommended for treatment of chronic, infectious respiratory disease that is unresponsive to conventional antibiotic treatment. In addition, it is recommended for prophylactic administration prior to stressful events that may impair pulmonary defense mechanisms, including weaning and long-distance transport. Propionibacterium acnes is considered an additive (adjunct) treatment to antibiotic therapy, not a stand alone treatment. Treatment requires a series of 3 injections over a period of approximately 1 week.
In addition to equine respiratory disease, P. acnes has been recommended for treatment of endometritis, osteomyelitis, papillomatosis (warts), abdominal abscess, fistulous withers, and sarcoid skin tumors. In this author’s experience, administration of P. acnes is effective for treatment of viral papillomatosis, whereas, efficacy for treatment of sarcoid skin tumors (intralesional and intravenous) is less consistent.
Inactivated Parapoxvirus ovis:
Parpoxvirus ovis (Zylexis™, Pfizer Animal Health) is a non-specific immunomodulator that contains a purified highly concentrated viral strain that is inactivated and packaged in a freeze dried form. In a respiratory challenge model of equine herpesvirus (EHV) infection, Zylexis™ was shown to reduce the severity of nasal discharge when compared with placebo-treated horses. The response of this treatment occurs rapidly after treatment and may be effective in less than 24 hours. Similar to other compounds Zylexis™ treatment requires a series of 3 treatments over approximately 10 days.
Respiratory disease and beyond
Interferon-alpha (IFN) is a naturally produced protein that has antiviral activity. Interferon production occurs naturally in all mammalian hosts, including horses. Synthesis of this protein is induced by viral infection, and is an early, nonspecific antiviral defense mechanism. Interferon-alpha aids with nonspecific immunity via enhanced killing activity of several types of white blood cells. Interferon- induces an antiviral state in target host cells by stimulating production of enzymes that inhibit viral protein synthesis and degrade viral RNA. In mice, administration of IFN stimulates white blood cells to produce other proteins that activate the cell response that promotes cellular killing and removal of microorganisms.
Interferon alpha can be used in a few different ways, by the mouth in low doses or systemically at higher doses. When the low doses are used by mouth the effects include: reduced inflammation in the lower respiratory tract of racehorses with pulmonary inflammation. This treatment reduces fluid and mucous in the respiratory tract, lowers total cell counts in lung fluid therby improving pulmonary health which may improve athletic performance. Interferon- administration is not effective with all airway conditions, so it is important to visit with your veterinarian to determine what tests are needed and if this therapy is right for your horse.
When IFN is given to the patient by the oral route an interesting effect is that it is not absorbed by the intestine, which is in contrast to many drugs that we administer to our equine patients. We know this because IFN is degraded by digestive enzymes and cannot be detected in peripheral blood after oral administration. Instead, oral dosing activates unique natural defense systems originating in the oral cavity (mouth). This anatomic region is a special component of the immune system called the oropharangeal-associated lymphoid tissue. White blood cells exposed to IFN transfer enhanced biologic effects to other naive white blood cells in the absence of IFN. Ultimately this therapy has a bit of a domino-effect from one activated white blood cell to another. This process requires direct cell-to cell-contact, which does not require continued presence of IFN. Cell-to-cell transfer of the antiviral state to naive cells permits low to undetectable concentrations of IFN to produce potent antiviral activity, and possibly represents a major mechanism for amplification natural IFN activity. White blood cells then enter general circulation and communicate this antiviral capability to cells at distant sites. This mechanism allows the biologic effects of IFN to reach tissues accessible to mobile white blood cells, in which penetration of IFN is poor, such as the surface of the respiratory tract, gastrointestinal tract, and eye.
Although this treatment is effective under various conditions, it is important to note that patients can become unresponsive to IFN therapy after repeated administration due to production of anti-IFN antibody (protein) or reduction in sensitivity of the immune system to the interferon that is given. These effects occur after the host has been exposed to a foreign protein (in this case IFN-α) several times. The effect of antibody production that limits the effectiveness of IFN has been observed in human patients and calves.
An additional use of interferon-α is a larger dose administration given systemically (intravensously). When used in high doses, this treatment can be beneficial for horses suffering from certain viral diseases, such as West Nile Virus encephalitis. Since we don’t have an effective antiviral drug for treatment of WNV, the use of a natural protein made by the immune system makes good sense. In the cases that have been managed with this therapy, the results have generally been favorable. Additional uses of immunstimulant agents including equine endometritis
Mycobacterial products have long been recognized as potent stimulators of nonspecific immunity. The bacteria Calmette-Guerin (BCG) vaccine was developed from a strain of Mycobacterium bovis that had been inactivated through serial passage (growth) in culture. Live BCG, whole-inactivated BCG, and mycobacterial cell wall fractions have been used as nonspecific immunostimulant agents, and all 3 preparations demonstrate strong activity when administered with antigen. The mechanism of action is white blood cell activation and subsequent release of immune stimulating proteins by the host, called cytokines. Whole, inactivated BCG preparations can be highly reactive; therefore, partial cell wall products have been developed that are less reactive. Purified peptides (tiny proteins) are the smallest subunit of the mycobacterial cell wall that maintains immunostimulant activity. In equine medicine, mycobacterial cell wall products are used to treat infectious respiratory disease (Equimune IVÒ, Bioniche, Belleville, ON, K8N 5J2) and sarcoid skin tumors (RegressinÒ, Bioniche, Belleville, ON, K8N 5J2).
Purified mycobacterial cell wall extract is labeled for single-dose, intravenous administration, as solo therapy for treatment of equine herpesvirus infection. Administration of purified mycobacterial cell wall extract improves clinical recovery of horses with respiratory disease resulting from stress, transportation, bacteria and/or viral infections. In an investigation looking at the efficacy of such preparations response to treatment was determined by monitoring clinical signs (fever, cough, anorexia, nasal discharge, abnormal auscultation, poor performance) and laboratory tests (complete blood count, differential, and acute phase protein concentration). More than half of the horses treated with mycobacterial cell wall extract improved significantly within approximately a week after administration of a single dose, whereas less than half of the saline treatment group were without clinical signs.
In human medicine, live BCG immunotherapy is used for treatment of certain tumors that affect the urinary system. In such patients, treatment with live BCG organisms prevents recurrence or progression of superficial bladder tumors, and the response is superior to treatment with certain chemotherapeutic agents. Complications may occur in patients that are treated multiple times with a certain BCG products, veterinary consultation will help avoiding complications with administration.
Mycobacterial cell wall extract
Settle® (Bioniche, Belleville, ON, K8N 5J2) has been studied for its effectiveness to treat endometritis in mares. Endometritis is classified as an infection of the innermost lining of the uterus. In certain mares, persistent infection of the uterus may impair reproductive soundness, so clearance of infection is an important mechanism to maintain reproductive health in infected mares. The most common bacterial pathogen associated with endometritis in horses is Streptococcus zooepidemicus. Settle has been shown to work well alone and in combination with standard therapies to clear infection of the uterine lining. This product can be used as a systemic treatment (intravenously) or locally (in the utuerus). Consultation with your veterinarian will help determine if this therapy is right for your mare.
Immunostimulant therapy may be beneficial for equine patients under a variety of settings that include prevention and treatment of various infectious diseases. It is important to know the appropriate use of such treatments so that the ideal immunostimulant preparation is selected for each individual patient. Determination of the factors of disease in your horse will be provided by appropriate veterinary evaluation. In some instances this method of treatment will work in combination with antimicrobial agents to enhance the clearance of pathogen challenge.