Human Recombinant Interleukin-2 Induces Maturation and Activation Signals for Feline Eosinophils In Vivo

Abstract

Immunotherapy, with interleukin-2 (IL-2) or IL-2 plus lymphokine-activated killer (LAK) cells, has been used to treat cancer and acquired immunodeficiency syndrome (AIDS) in man. Similarities between feline leukemia virus (FeLV) infection in the cat and human immunodeficiency virus (HIV) infection in man have prompted immunotherapeutic studies in the cat. To develop baseline data on hematological responses to infused IL-2, cats were given daily (1-14 days) i.v. injections of 5 x 10(4) U/kg of recombinant human IL-2 (rHulL-2). Complete blood cell (CBC) counts were done weekly. Red blood cell (RBC), neutrophil, and lymphocyte numbers did not change appreciably over the course of the study. In contrast, rHulL-2 caused an eosinophilia in all but the 1 day treatment group. Treatment for 3 days generated a transient eosinophilia on day 7 that returned to baseline by 3 weeks. Five day and 7 day treatments generated an eosinophilia by day 7 that peaked on day 14 and returned to normal values by day 28. Treatment of cats for 14 days did not increase the magnitude or duration of the eosinophilia beyond the 5 or 7 day treatments. Bone marrow (BM) biopsies from rHulL-2-treated cats revealed a marked selective hyperplasia of eosinophil precursors. In the 5 day treatment group, all maturation stages of eosinophils were elevated by week 1 of treatment. By week 2, the early stages had returned to normal, whereas the late stage cells remained elevated, suggesting an ordered maturation response. Numbers of all eosinophil precursors approximated pretreatment numbers by weeks 3-4. Thus the BM hyperplasia preceded the blood eosinophilia by 1 week, suggesting that an enhanced maturation response of BM eosinophil precursors is a major contributor to the rHulL-2-induced blood eosinophilia. In addition to a maturation signal, rHulL-2 induces a potent activation signal for eosinophils as measured by a decrease in density and an increase in longevity in culture. The significance of the activated eosinophil in the therapeutic or toxicologic response to rHulL-2 infusion is discussed.

Eosinophils: A review

“…Interleukin 5, previously known as eosinophil differentiation factor (Spry, 1988), is the principal cytokine that specifically stimulates the proliferation and differentiation of committed eosinophil progenitors (Warren and Moore, 1988;Weller, 1991). Although the role of interleukin 2 is not yet fully defined with regard to eosinophilopoiesis, injection of this substance into rats, cats and humans induces systemic and peripheral eosinophilia (Anderson and Hayes, 1989;Tompkins et al, 1990). Interleukin 2 acts by stimulating T cells to produce GM-CSF and interleukin 5 (MacDonald et al, 1990).…”

“…It is hypothesized that autochthonous lymphocytes regulate the release of products from eosinophils, and so play a major role in the pathophysiology of eosinophil-associated diseases (Silberstein and David, 1987;Frew and Kay, 1988). Multisystemic eosinophil infiltration and/or eosinophilia produced in rats and cats following the administration of the T cell lymphokine, interleukin-2 (Anderson and Hayes, 1989;Tompkins et aL, 1990) is mediated by the production of interleukin 5 and GM-CSF from T lymphocytes (MacDonald et aL, 1990). The ability of eosinophils to synthesize de novo CD4 and HLA-DR protein (a class II MHC protein) (Lucey et aL, 1989a;Lucey et al, 1989b) is of major significance with regard to eosinophil-lymphocyte interaction.…”

Transmission and Immunopathogenesis of FIV in Cats as a Model for HIV

“…The course of FIV infection can be predicted by plasma viremia, CD4+ T cell counts, CD4/CD8 ratio, antiviral immune responses, and clinical signs. The acute phase is recognized by an early peak viremia that precedes the onset of clinical signs, decline in the numbers of CD4+ T cells, and detection of virus in blood lymphocytes [56,59,73,228]. Productive infection is seen within the thymus, mucosal and systemic lymphoid tissue, bone marrow, and central nervous system [11,56,168,252] and virus can be detected in saliva, vaginal secretions, semen, cerebrospinal fluid, and milk/colostrum [32,33,62,121,163].…”

Measurement of Feline Serum Interleukin-5 Level

“…These results imply that feline peripheral eosinophils may be regulated by a factor other than IL-5. Tompkins et al reported that cats given daily intravenous injections of recombinant human IL-2 showed transient eosinophilia [18]. It is reported that eosinophils express the IL-2 receptor CD 25, and IL-2 acts as a chemoattractant for eosinophils in humans [8].…”