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M B Tompkins

Publications and source records attributed to M B Tompkins.

14 recordsLinked to original sources
PubMed1992

Immunization-induced decrease of the CD4+:CD8+ ratio in cats experimentally infected with feline immunodeficiency virus.

In a previous experiment a group of 15 specified pathogen free (SPF) cats were experimentally infected with a Swiss isolate of feline immunodeficiency virus (FIV). A group of 15 SPF cats served as FIV negative controls. Nine cats of each group were vaccinated with a recombinant feline leukemia virus (FeLV) vaccine, six cats in each group with a placebo vaccine. All vaccinated cats developed high antibody titers to FeLV and were protected against subsequent FeLV challenge infection. In both control groups five of six cats became persistently infected with FeLV. Unexpectedly, the primary immune response to the vaccine antigen was significantly higher in the FIV positive group than in the FIV negative. The secondary response was stronger in the FIV negative cats. The goal of the present investigation was to further study the immune response in these 30 cats. They were immunized twice with the synthetic peptide L-tyrosine-L-glutamic acid-poly(DL-alanine)-poly(L-lysine) (TGAL) 21 days apart. Blood samples were collected on four occasions during the immunization process. They were tested for antibodies to TGAL, complete blood cell counts and CD4+, CD8+ and pan-T-lymphocyte counts. The following observations were made: (1) in contrast to the FeLV vaccine experiment, the primary immune response to TGAL was not significantly stronger in the FIV positive cats when tested by enzyme-linked immunosorbent assay (2). The absolute size of the CD4+ lymphocyte population was distinctly smaller in the FIV positive than in the FIV negative cats. The lowest CD4+ values were found in the dually FIV/FeLV infected cats. (3) A population of CD8+ lymphocytes was identified that was characterized by a distinctly weaker fluorescence. The size of this population increased in FIV positive and decreased in FIV negative cats during the TGAL immunization experiment. (4) The CD4+:CD8+ ratio increased in FIV negative cats during TGAL immunization from 1.9 to 2.3. In contrast, in FIV positive animals the CD4+:CD8+ ratio decreased significantly from 1.9 to 1.3 during the same period. From these and earlier data it was concluded that in short-term FIV infection the immune response to T-cell dependent antigens may be increased over that of the controls. Immune suppression develops gradually with duration of the infection. The significant drop of the CD4+:CD8+ ratio over a 5 week immunization period suggests that antigenic stimulation may accelerate the development of immune suppression in FIV positive cats. If this is a general feature, FIV infection may provide a particularly interesting model for studying the pathogenesis of AIDS.

Amino Acid Sequence↗
PubMed1991

Early events in the immunopathogenesis of feline retrovirus infections.

Feline leukemia virus and feline immunodeficiency virus (FIV) are lymphotropic retroviruses that cause a wide range of diseases in domestic cats. Although it is known that both viruses are capable of infecting T lymphocytes and that infected cats are lymphopenic, it was not known how infection with either virus might alter specific lymphocyte subpopulations. Using a panel of monoclonal antibodies to feline lymphocyte subpopulations, we examined, by use of flow cytometric analysis, lymphocyte changes in cats naturally infected with FeLV or FIV and explored the early stages in the immunopathogenesis of experimentally induced infection with these viruses. Both groups of naturally infected cats had T-cell lymphopenia. In the FIV-infected cats, the T-cell decrease was principally attributable to loss of CD4+ cells, whereas CD8+ and B-cell numbers remained normal. This led to inversion of the CD4+ to CD8+ ratio in these cats. In contrast, the T-cell lymphopenia in FeLV-infected cats resulted from decrease in CD4+ and CD8+ cells, which led to a CD4+ to CD8+ ratio within normal limits. Experimentally induced infection with these 2 viruses supported these findings. Infection with FIV induced early (10 weeks after infection), chronic inversion of the CD4+ to CD8+ ratio. In contrast, infection with FeLV did not alter CD4+ to CD8+ ratio in the first 20 weeks after infection.

Animals↗
PubMed1990

Human recombinant interleukin-2 induces maturation and activation signals for feline eosinophils in vivo.

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.

Animals↗
PubMed1990

Characterization of monoclonal antibodies to feline T lymphocytes and their use in the analysis of lymphocyte tissue distribution in the cat.

We describe the development of three monoclonal antibodies to feline T lymphocytes. Antibody 1.572 stains 93% of feline thymocytes, 49% of lymph node, and 65% of spleen lymphocytes. Two-color analysis shows 1.572 does not stain Ig-bearing cells, and 1.572-positive lymphocytes plus Ig-positive lymphocytes make up approximately 90% of peripheral blood lymphocytes (PBL), suggesting that 1.572 is a pan-T cell marker. The other two monoclonal antibodies, 3.357 and CAT30A, stain a smaller population of thymocytes (59%) of which 40% express both antigens. The 3.357 antigen is found on 23% of lymph node and 47% of spleen lymphocytes, while the CAT30A antigen is found on 29% of lymph node and 19% of spleen lymphocytes. Two-color analysis shows that 3.357 and CAT30A stain mutually exclusive subpopulations of 1.572-positive cells. Using thymocytes as an antigen source, antibody 3.357 precipitated a molecule of 66,000 molecular weight (Mw) under nonreducing conditions and a heterodimer of 32,000 and 34,000 under reducing conditions, suggesting that 3.357 recognizes the feline CD8 homologue. Antibody CAT30A precipitated a molecule of 55,000 Mw under both reducing and nonreducing conditions, which suggests it recognizes the feline CD4 homologue. Analysis of PBL profiles of 35 normal cats using the three monoclonal antibodies indicates that the distribution of feline PBL subpopulations is similar to man, including the CAT30A:3.357 ratio (1.74), which is identical to reported CD4:CD8 ratios in man. Based on these data, the feline CD4 and CD8 homologues are similar to those reported in other species.

Animals↗
PubMed1990

Zidovudine toxicity to cats infected with feline leukemia virus.

Feline leukemia virus (FeLV) infection of cats is a model for the acquired immunodeficiency syndrome in humans. The toxicity of zidovudine was evaluated in SPF cats experimentally infected with FeLV. At initiation of the zidovudine study, all cats were antibody positive for FeLV antigens but clinically asymptomatic. Four cats were also viremic. Thirteen, 6- to 10-month-old cats were divided into five dosage groups and given zidovudine po at 0, 7.5, 15, 30, or 60 mg/kg daily in three equally divided doses for 32 to 34 days. Titers of circulating virus antigen remained constant; however, three of six cats receiving the higher doses of zidovudine (greater than or equal to 30 mg/kg) showed an increase in antibody titers to FeLV. Administration of zidovudine resulted in a progressive anemia, dependent upon dose and time. Macrocytes were observed prior to the development of anemia and were also found in several nonanemic cats. Repeated measures regression analyses indicated that an increased dose of zidovudine was associated with decreased packed cell volume, red blood cell count, and hemoglobin. As determined from the packed cell volume, the analyses indicate that anemia is induced only by the two highest doses of zidovudine. The regression model indicates that daily doses of 60 and 30 mg/kg are expected to induce anemia by Day 4 and Day 13, respectively. Progressive absolute neutropenia was observed in the greater than or equal to 30 mg/kg groups. Histopathologic lesions consisted of marked bone marrow hypercellularity in cats given greater than or equal to 30 mg/kg zidovudine and splenic extramedullary hematopoiesis in cats given greater than or equal to 15 mg/kg. Thus, oral toxicity of zidovudine in the cat is manifested by a dose-related anemia and neutropenia as observed in humans.

Anemia↗
PubMed1990

Lymphocyte population changes in cats naturally infected with feline immunodeficiency virus.

Feline immunodeficiency virus (FIV) is associated with feline acquired immunodeficiency syndrome (FAIDS) and has been suggested as a model for HIV-induced human AIDS. The most obvious immunological defect in HIV infection is a reduction in CD4+ cell numbers and an inversion of the CD4:CD8 ratio. To determine whether the same is true in FIV infection, we analyzed by flow cytometry using a panel of monoclonal antibodies to feline lymphocyte populations the CD4:CD8 ratios in cats naturally infected with the virus. We report that 13 of 19 FIV-infected cats had ratios below the 5th percentile of normal cats (0.57, established from analysis of 39 normal cats) and 18 of 19 had ratios below 1. Repeated analyses over a period of several months revealed the inverted ratios to be consistent. Analysis of lymphocyte numbers in FIV-infected cats shows that the inverted ratios are due to a decrease in CD4+ T cells, while CD8+ T and B cells remain relatively normal in number. Analysis of a group of cats with a variety of other chronic diseases, including feline leukemia virus (FeLV) infections, revealed a near-normal distribution of CD4:CD8 ratios. These findings are similar to those in HIV infections and indicate that, like HIV, FIV causes a selective reduction in CD4+ cells and should be an excellent model for studying retrovirus-induced AIDS.

Animals↗
PubMed1989

Feline cytotoxic large granular lymphocytes induced by recombinant human IL-2.

Large granular lymphocytes (LGL) have been characterized phenotypically and functionally as cytotoxic T lymphocytes, NK cells or lymphokine-activated killer cells. The most prominent morphologic feature of LGL is large cytoplasmic granules that are thought to contain the molecules responsible for cell lysis. In this study, we describe the morphologic and functional characteristics of IL-2-dependent cytotoxic lymphocytes derived from feline PBL. Stimulation of feline PBL with Con A followed by culturing in 50 U of gibbon monkey IL-2 human rIL-2 induced long term lymphocyte cultures. These lymphocytes are cytotoxic for the feline leukemia virus-induced T cell lymphoma (FL74), in a 4-h 51Cr release assay. All cell lines are either constitutively cytotoxic for FL74 cells, or cytotoxic in a lectin-dependent cell cytotoxic assay, the latter being a characteristic of low passage cultures. In contrast, no cell lines express self lysis or lysis for other lines. [3H]TdR uptake showed that 1 U of human rIL-2 produces a 50% maximal proliferative response by feline lymphocytes suggesting a high degree of homology between the ligand binding sites of feline and human IL-2R. Feline cytotoxic lymphocytes possess abundant cytoplasm containing large azurophilic granules characteristic of LGL. These granules are bound by a bilipid membrane and contain numerous smaller membrane-bound vesicles 50 to 60 nm in diameter. A model is proposed, whereby subsequent to binding of LGL to target cell the large granules fuse to the LGL plasma membrane and release the small vesicles into the binding pocket. The vesicles then transport the lytic molecules directly and selectively to the target cell membrane.

Animals↗
PubMed1989

Interleukin-2 suppression in cats naturally infected with feline leukemia virus.

Feline peripheral blood lymphocytes (PBLs) produce interleukin-2 (IL-2) when stimulated with concanavalin A (Con A) or the combination of the Ca2+ ionophore A23187 (A2) plus the phorbol ester phorbol-12-myristate-13-acetate (PMA). To determine the status of T helper cell function in cats naturally infected with feline leukemia virus (FeLV), PBLs from 19 normal cats and 49 FeLV-infected (34 asymptomatic and 15 symptomatic) cats were tested for their ability to produce IL-2 in response to Con A or A2/PMA stimulation. In the case of Con A stimulation, 21, 41, and 67% of normal, FeLV-infected asymptomatic, and FeLV-infected symptomatic cats, respectively, failed to produce detectable levels of IL-2. In contrast, A2/PMA stimulation yielded high titers of IL-2 in 100% of the normal cats, 92% of asymptomatic cats, but only 44% of clinically ill cats. All of the A2/PMA nonresponders in the FeLV-infected symptomatic population were also unresponsive to Con A. T Helper immunosuppression was observed in cats with FeLV-induced lymphoproliferative diseases as well as cats with FeLV-associated acquired immune deficiency syndrome-like diseases. These data suggest that TH immunosuppression in naturally infected viremic cats may precede development of clinical disease. Moreover, the ability to restore TH function with A2/PMA is diminished with development of clinical disease.

Animals↗
PubMed1988

Clinical and immunologic aspects of FeLV-induced immunosuppression.

Cats exposed to the feline leukemia virus (FeLV) may mount an effective immune response and eliminate the virus, develop a non-viremic, latent infection or become persistently infected and shed the virus. Persistently infected cats commonly die of secondary opportunistic infections that result from FeLV-induced immunosuppression. The acquired immunosuppression is the most frequent and most devastating consequence of FeLV infection in the cat. Immunosuppression is targeted primarily to the cell-mediated immune system and has been attributed to the viral p15e envelope protein. The decreased IgG response and proliferative response to T cell mitogens is thought to be due to a defect in the helper cell function. As a result of T helper cell immunosuppression, infected cats may also have defective cytotoxic lymphocyte and activated macrophage functions which are regulated by their lymphokines. Research has shown that the virus causes a general suppression in the production of T cell-derived lymphokines, including gamma interferon and interleukin 2. A decrease in the function of polymorphonuclear leukocytes has also been reported and may contribute to deaths due to opportunistic infections in FeLV-positive cats. There are numerous parallels between the acquired immunodeficiency syndrome (AIDS) in man and the FeLV-induced immunodeficiency syndrome in cats. Frequent deaths due to opportunistic infections, lymphopenia, depressed cell-mediated immune responses to T cell-dependent antigens despite hypergammaglobulinemia and the presence of a long period of time between infection and the onset of clinical signs are just a few of the syndromes that are similar between the 2 retroviral diseases. A new strain of FeLV, FeLV-FAIDS has been associated with a naturally occurring immunosuppressive syndrome that is strikingly similar to AIDS in man. In addition, a T-lymphotropic retrovirus has recently been identified from cats with an immunodeficiency-like syndrome; this feline lentivirus disease is morphologically similar, but antigenically distinct from the human immunodeficiency virus, the cause of AIDS. Treatment for FeLV immunosuppression is primarily supportive. The development of a soluble tumor cell antigen vaccine has been shown to be efficacious in preventing FeLV infections.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Oral use of human alpha interferon in cats.

Low doses (0.5 or 5.0 U) of human alpha interferon (HuIFN alpha) given orally prevented the experimental development of fatal feline leukemia virus (FeLV)-related disease. Twenty-one FeLV-susceptible cats were inoculated with the Rickard strain of FeLV. Cats given oral HuIFN alpha survived significantly (p less than 0.001) longer than untreated FeLV-infected cats. Moreover, only 4 of 13 (30.8%) HuIFN alpha-treated cats developed clinical disease during the course of the study, whereas 100% of the untreated control cats developed fatal FeLV-related disease. Thus, in experimental retroviral disease, heterologous species HuIFN alpha provided significant clinical benefits.

Administration, Oral↗
PubMed1987

Induction of IL-2 and lymphokine activated killer cells in the cat.

We have described the use of a cloned murine IL-2-dependent T-cell line to directly measure feline IL-2. Concanavalin A stimulated feline peripheral blood lymphocytes produced an IL-2-rich supernatant that supported the growth of this murine IL-2-dependent T-cell line. In addition to producing IL-2, Con A stimulated killer cells in PBL were cytotoxic for the FeLV transformed tumor cell line FL74. Incubating feline PBL with a cocktail of the calcium ionophore A23187 and phorbol ester also led to the generation of cytotoxic cells as well as the production of high levels of IL-2. Finally, IL-2-rich supernatant was able to stimulate cytotoxic activity in PBL from normal cats.

Animals↗
PubMed1985

Stimulation of a cell-mediated cytotoxic response to FeLV-induced T cell lymphomas in the cat.

Nonspecific cell-mediated cytotoxicity was examined in the peripheral blood and spleens of normal and vaccinia virus-infected adult domestic cats. Natural cytotoxic (NC)-like cells, as measured by lysis of vaccinia- or HSV-infected, adherent cat tongue cells, were found in both the spleen and peripheral blood of normal, nonimmune cats. Cytotoxicity was expressed in a 16-hr assay but not in a 4-hr assay. Natural killer (NK)-like cells, as measured by lysis of an FeLV-induced lymphoid tumor cell line (FL-74) growing in suspension, were found in the spleen but not PBL, and required a 16-hr assay for expression. Infection with vaccinia virus did not increase the activity of feline NC-like cells in either the peripheral blood or the spleen. NK-like function, however, was increased. Cytotoxicity peaked 6 days post-infection and required a 16-hr assay for maximal expression of cell lysis. Furthermore, a cell with cytotoxic characteristics of the spleen NK-like cell appeared at low levels in the circulation at 6 days post-vaccinia infection. NK-like cells from vaccinia-infected cats showed some cytotoxicity for FL74 targets in a 4-hr assay. The cat thus possesses at least two functionally different populations of naturally cytotoxic cells. NC-like cells are found in the spleen and peripheral blood, lyse virus-infected monolayer targets, and are not activated by infection. NK-like cells are found in the spleen, lyse-lymphoid tumor targets, and can be activated by infection, with their peak activity occurring 6 days after infection.

Animals↗
PubMed1983

Natural cell-mediated cytotoxicity in the domestic cat: properties and specificity of effector cells.

Using a 51Cr-release microcytotoxicity assay, natural cytotoxic cell activity was demonstrated in the peripheral blood of clinically normal, nonimmune cats. Cytotoxicity was enhanced against virus-infected feline cells over that in noninfected cells. Xenogeneic mouse and hamster target cells were also susceptible to lysis. The cytotoxic activity increased as effector-to-target cell ratios were increased and required a 16-hour assay to be expressed. The specificity of the natural cytotoxicity was selective in that some, but not all, target cells tested were susceptible to lysis. Characterization of the cytotoxic cells showed them to be nonadherent and to possess Fc receptors for immunoglobulin G.

Animals↗