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Chemokines play an important role in the immune system by regulating cell trafficking in homeostasis and inflammation. In this study, we report the identification and characterization of a novel cytokine-like protein, DMC (dendritic cell and monocyte chemokine-like protein), which attracts dendritic cells and monocytes. The key to the identification of this putative new chemokine was the application of threading techniques to its uncharacterized sequence. Based on our studies, DMC is predicted to have an IL-8-like chemokine fold and to be structurally and functionally related to CXCL8 and CXCL14. Consistent with our predictions, DMC induces migration of monocytes and immature dendritic cells. Expression studies show that DMC is constitutively expressed in lung, suggesting a potential role for DMC in recruiting monocytes and dendritic cells from blood into lung parenchyma.

Objective: Ex vivo and in vivo micro-computed tomography (micro-CT) combined with a novel image analysis algorithm were used to quantify cortical bone loss and periosteal new bone formation for therapeutic evaluation in a murine model of collagen-induced arthritis., Methods: An automated algorithm was created to locate 5 metatarsophalangeal and 3 metacarpophalangeal joints in 3-dimensional micro-CT images of mouse paws for evaluation of joint cortical bone volume (JCBV) within close proximity of the joints as well as cortical bone mineral density and periosteal new bone formation within the paws. For validation, automated estimates of JCBV were compared with radiographic visual scores (RVS) in 4 treatment groups (n = 9 per group): rat anti-mouse CD11a monoclonal antibody, methotrexate (MTX), anti-CD11a plus MTX, and saline only. In a separate study, serial images of hind limbs were evaluated in 2 treatment groups: murine tumor necrosis factor receptor II-Fc fusion protein (mTNFRII; n = 10) and control antibody (n = 7)., Results: Automated estimates of the JCBV were significantly correlated with the RVS (hind paws R = -0.94, front paws R = -0.81, combined R = -0.87). The anti-CD11a group had significantly higher JCBV compared with controls. In the serial study, the automated estimate of JCBV detected significant treatment effects in the mTNFRII-Fc group compared with controls. Cortical bone mineral density was significantly higher in all treatment groups compared with controls., Conclusion: Micro-CT combined with a novel image analysis technique (estimation of JCBV) provides a fully automated means to quantify bone destruction in a mouse model of rheumatoid arthritis., (Copyright 2004 American College of Rheumatology)

Mucosal infection by feline immunodeficiency virus (FIV) was assessed via a single exposure of the vaginal or rectal mucosa to either infectious peripheral blood mononuclear cells (PBMCs), infectious plasma, or cell-free cultured virus. All cats inoculated with cell-free cultured virus (100 or 400 TCID) and 9 of 10 cats inoculated with infected PBMCs (2 x 10(7) or 2 x 10(5)) became persistently viremic within 3 weeks. Neither cat inoculated with 2 x 10(3) PBMCs became viremic. Rectal and vaginal exposure were equally effective routes to induce viremia. CD4+ T cells and mitogen-stimulated PBMC proliferation declined in all infected cats. However, a transient PBMC proliferative response to FIV p24gag occurred in most virus-exposed cats, especially those that did not develop detectable infection. FIV was not transmitted by mucosal exposure to infectious virus in plasma (100 TCID), a dose > 10-fold that needed for infection by parental injection. In vitro studies suggested that a plasma heat-stable virus-neutralizing factor may be associated with failure of plasma virus to establish infection via the mucosal route. Mucosal FIV infection provides a new model with which to study early stages of infection and intervention in transmucosal lentivirus infections.

Viral RNA load has been shown to indicate disease stage and predict the rapidity of disease progression in human immunodeficiency virus type 1 (HIV-1)-infected individuals. We had previously demonstrated that feline immunodeficiency virus (FIV) RNA levels in plasma correlate with disease stage in infected cats. Here we expand upon those observations by demonstrating that plasma virus load is 1 to 2 logs higher in cats with rapidly progressive FIV disease than in long-term survivors. Differences in plasma FIV RNA levels are evident by 1 to 2 weeks after infection and are consistent throughout infection. We also evaluated humoral immune responses in FIV-infected cats for correlation with survival times. Total anti-FIV antibody titers did not differ between cats with rapidly progressive FIV disease and long-term survivors. These findings indicate that virus replication plays an important role in FIV disease progression, as it does in HIV-1 disease progression. The parallels in virus loads and disease progressions between HIV-1 and FIV support the idea that the accelerated disease model is well suited for the study of therapeutic agents directed at reducing lentiviral replication.

We studied vertical transmission of feline immunodeficiency virus (FIV) to determine whether it might provide a model with which to study intervention strategies for mother-to-offspring transmission of human immunodeficiency virus (HIV). We found that pregnant cats acutely infected with FIV (FIV-CSU-2771) transmitted the virus to their offspring via both prenatal and postnatal routes. In utero transmission led to several pathogenic consequences including arrested fetal development, abortion, stillbirth, subnormal birth weights, and birth of viable, virus-infected, and asymptomatic but T cell-deficient kittens. Postnatal milk-borne FIV transmission was demonstrated by the presence of cell-free and cell-associated virus in colostrum and milk and through a foster-nursing experiment. The potential for intrapartum FIV transmission was documented by frequent virus isolation from vaginal wash cells in both the pre- and postpartum periods. FIV transmission was efficient during acute maternal infection, leading to an overall infection rate of 70%. We conclude that FIV vertical transmission may be a useful model with which to evaluate intervention strategies for HIV transmission from mother to child.

Development of feline immunodeficiency virus (FIV) infection in cats as a small animal model for lentiviral immunodeficiency disease has been hampered by the prolonged and variable disease course following experimental infection. To address this issue, we generated high-titer, unselected FIV stocks by pooling plasma from cats acutely infected with a subgroup C FIV isolate designated CABCpadyOOC (FIV-C-PGammer). Subsequent infection with this virus pool resulted in rapidly progressive, fatal disease in greater than 50% of infected cats. Accelerated FIV disease was characterized by rapid and progressive CD4+ T-cell loss, lymphadenopathy, weight loss, lymphoid depletion, and severe thymic atrophy. Mortality and rate of disease progression were affected by the age of each cat at infection and whether the virus source animal was in the acute or chronic stage of infection. The rapid FIV disease syndrome was consistently associated with systemic lymphoid depletion, clinical disease, and susceptibility to opportunistic infections, analogous to accelerated and/or terminal HIV-1 infection. The results of this study demonstrate that FIV infection is a valid small animal model for lentiviral immunodeficiency disease.

Cats infected with feline immunodeficiency virus (FIV) develop a disease syndrome similar to that caused by human immunodeficiency virus type 1 (HIV-1) infection in humans. HIV-1 replication has been shown to correlate with the disease stage and progression. To assess replication kinetics and disease progression in early FIV infection, we developed a quantitative competitive reverse transcriptase PCR to measure the plasma virus load at serial time points after virus exposure. We found that an early peak viremia immediately preceded the onset of acute-phase symptoms in infected cats. Plasma virus levels remained high throughout the symptomatic phase of infection, which lasted for 8 to 10 weeks, and then declined as clinical symptoms resolved; however, all cats maintained significant plasma virus titers through 36 weeks postinfection. Early peak viral replication coincided with the initial precipitous decline in circulating CD4+ T lymphocytes. These results indicate that FIV kinetics are similar to those of HIV-1 during the acute and secondary phase of infection and that the plasma FIV load correlates with the disease stage. These results serve to further develop the FIV model and to enhance its usefulness for pathogenesis, vaccine development, and therapeutic studies related to HIV.

We studied vertical transmission of feline immunodeficiency virus (FIV) to determine whether it might provide a model with which to study intervention strategies for mother-to-offspring transmission of human immunodeficiency virus (HIV). We found that pregnant cats acutely infected with FIV (FIV-CSU-2771) transmitted the virus to their offspring via both prenatal and postnatal routes. In utero transmission led to several pathogenic consequences including arrested fetal development, abortion, stillbirth, subnormal birth weights, and birth of viable, virus-infected, and asymptomatic but T cell-deficient kittens. Postnatal milk-borne FIV transmission was demonstrated by the presence of cell-free and cell-associated virus in colostrum and milk and through a foster-nursing experiment. The potential for intrapartum FIV transmission was documented by frequent virus isolation from vaginal wash cells in both the pre- and postpartum periods. FIV transmission was efficient during acute maternal infection, leading to an overall infection rate of 70%. We conclude that FIV vertical transmission may be a useful model with which to evaluate intervention strategies for HIV transmission from mother to child.

Cats infected with the highly pathogenic feline leukemia virus isolate FeLV-FAIDS develop an immunodeficiency syndrome characterized by progressive loss of CD4+ T cells and eventual pan-lymphocyte depletion. Prior to the decline in circulating CD4+ cells, infected cats are unable to mount primary antibody responses to T-dependent antigens. We investigated whether the altered ability of helper T cells to produce cytokines necessary for B cell growth and differentiation might be a primary event in the pathogenesis of FeLV-FAIDS infection. We found that as early as 9 weeks after infection, lymphocytes from cats with normal CD4+ cell numbers produced significantly lower levels of B-cell stimulatory factors. This deficit became progressively more severe with time. By contrast, resting B cells isolated from infected cats did not differ from controls in the ability to undergo activation and differentiation to antibody-secreting cells. The results suggest that a progressive defect in Th function occurs prior to CD4+ T-cell depletion early in the course of FeLV-FAIDS induced immunodeficiency.