Showing papers by "William J. Murphy published in 1997"

A molecular phylogeny for aplocheiloid fishes (Atherinomorpha, Cyprinodontiformes): the role of vicariance and the origins of annualism.

Abstract: Annual aplocheiloid killifish embryos possess a rare ability among vertebrates to enter stages of developmental arrest (diapause) when subjected to adverse environmental conditions. Previous morphological analyses have presented disparate hypotheses regarding the evolution of the intriguing life history associated with this phenomenon. We present a novel hypothesis of aplocheiloid relationships based on 1,009 bp of sequence data from three mitochondrial genes (cytochrome b, 12S rRNA, and 16S rRNA). Phylogenetic analysis using maximum parsimony, neighbor-joining, and maximum likelihood produce strongly congruent topologies. Our data confirm the monophyly of the Neotropical family Rivulidae, while demonstrating a paraphyletic Old World assemblage. The basal sister group position of Indo-Malaysian and Madagascaran taxa relative to a monophyletic South American/African dichotomy strongly indicates the role of vicariance in the diversification of these fishes in spite of their definition as secondary freshwater fish. The distribution of annualism onto this topology implies a single early origin for this suite of characters, prior to the divergence of South American and African taxa. If so, then annualism has since been lost several times during the evolution of genera now residing in permanent aquatic habitats. Paleoclimatic knowledge complements this scenario based on molecular characters.

The potential role of NK cells in the separation of graft-versus-tumor effects from graft-versus-host disease after allogeneic bone marrow transplantation.

Abstract: Allogeneic bone marrow transplantation (BMT) is being increasingly used for the treatment of a variety of cancers ranging from leukemias to breast cancer. However, significant obstacles currently limit the efficacy of this treatment procedure. The predominant two are the occurrence of graft-versus-host disease (GVHD) and relapse from the cancer. While regimens exist that prevent the occurrence or severity of GVHD, these same regimens also increase the rate of relapse. Conversely, most attempts to reduce the relapse rate also result in increased GVHD. The use of NK cells as an adoptive immunotherapy after BMT is attractive for several reasons. NK cells exhibit antitumor effects both in vitro and in animal models and may, therefore, promote graft-versus-tumor (GVT) effects to remove minimal residual disease after allogeneic BMT. NK cells have also been shown to promote hematopoietic engraftment and donor cell reconstitution after allogeneic BMT in mice. The effects of NK cells on hematopoiesis are believed to be due to the hematopoietic growth factors they can produce after activation. Another advantage in using NK cells is that they can prevent the occurrence of GVHD after allogeneic BMT in mice. This effect is mediated at least in part by the immunosuppressive cytokine, transforming growth factor beta (TGF-beta). BMT studies in mice also indicate that the beneficial effects of NK cells are optimal if they are administered soon after the transplant. Thereafter, NK cells and, more importantly, IL-2, which is used to activate them, are detrimental and can exacerbate the subsequent GVHD. Thus, the use of activated NK cells after allogeneic BMT may provide GVT effects without inducing GVHD.

Prospects for cytokine and chemokine biotherapy.

Abstract: Cytokines with immunostimulating effects have the capacity to induce tumor immunity in animal models, whereas some cytokines interfere with tumor growth based on their angiostatic effects. Despite these capabilities, cytokines, such as IFN-, IFN-, tumor necrosis factor, interleukin (IL)-1, and IL-2, have had limited clinical efficacy and many undesirable side effects. In preclinical models, cytokines can even promote tumor growth and increase metastatic spread. Although chemokines have had limited clinical evaluation, studies of animal models show that they can also have tumor-suppressive or tumor-enhancing effects. In mice, chemokines, such as IP-10, RANTES, and TCA3, have resulted in tumor regression and immunity to subsequent tumor challenge. Those chemokines that are angiostatic (e.g., PF4, IP-10, and MIG) can also induce tumor regression by reducing the tumor blood supply. Conversely, IL-8, which is angiogenic, can promote tumor growth. Our studies show that nasopharyngeal cell line cells (FADU) show a chemotactic as well as a proliferative response to MCP-1. In addition, a variant murine T cell lymphoma cell line Esb-MP, unlike the parental variant Esb, was selectively chemoattracted by murine MCP-1/JE. When injected s.c. into mice, the Esb-MP variant metastasized to the kidney with much higher frequency than the Esb variant. Both cultured kidneys from normal mice and a mesangial cell line constitutively produced chemoattractants that acted on Esb-MP but not Esb parental cells. Purification to homogeneity of these chemoattractants led to the identification of RANTES and JE. These results demonstrate that some chemokines may promote tumor growth and organ-specific metastatic spread of those tumors that have adapted and become responsive to chemokines. Finally, tumors appear to use numerous adaptive mechanisms to subvert and suppress the immune system. More effective therapy with cytokines and chemokines will require better characterization of the means by which tumors develop resistance to cytokines and overcome the immune system. Only then can we develop appropriate therapeutic approaches to antagonize cancer-induced immunosuppression.

Immunologic and hematopoietic effects of CD40 stimulation after syngeneic bone marrow transplantation in mice.

Abstract: CD40 is a molecule present on multiple cell types including B lymphocyte lineage cells CD40 has been shown to play an important role in B cell differentiation and activation in vitro, although little is known concerning the effects of CD40 stimulation in vivo We therefore examined the effects of CD40 stimulation in mice using a syngeneic bone marrow transplantation (BMT) model in an effort to augment B cell recovery after high dose therapy with hematopoietic reconstitution After the BMT, mice were treated with or without 2-6 microg of a soluble recombinant murine CD40 ligand (srmCD40L) given intraperitoneally twice a week A significant increase in B cell progenitors (B220+/ surface IgM-) was observed in the bone marrow of mice receiving the srmCD40L The treated recipients also demonstrated improved B-cell function with increases in total serum immunoglobulin and increased splenic mitogen responsiveness to LPS being noted Additionally, srmCD40L treatment promoted secondary lymphoid organ repopulation, accelerating germinal center formation in the lymph nodes Total B cell numbers in the periphery were not significantly affected even with continuous srmCD40L administration Lymphocytes obtained from mice treated with the ligand also had increases in T cell mitogen and anti-CD3 mAb responsiveness and acquired the capability to produce IL-4 Surprisingly, treatment with srmCD40L also produced hematopoietic effects in mice, resulting in an increase of BM and splenic hematopoietic progenitor cells in the mice after BMT Treatment with srmCD40L significantly increased granulocyte and platelet recovery in the peripheral blood Incubation of BMC with srmCD40L in vitro also resulted in increased progenitor proliferation, demonstrating that the hematopoietic effects of the ligand may be direct Thus, stimulation of CD40 by its ligand may be beneficial in accelerating both immune and hematopoietic recovery in the setting of bone marrow transplantation

Effects of CD40 Stimulation in the Prevention of Human EBV-Lymphomagenesis

Abstract: CD40 is a molecule present on B lineage cells, both normal and neoplastic. Signalling through CD40 has been demonstrated to promote B cell growth and differentiation in vitro. In contrast to its effects on normal B cells, we have found that CD40 stimulation can inhibit the growth of various aggressive histology human B cell lymphomas both in vitro and in vivo. Moreover, using a humadmouse chimera model in which human EBV-induced B cell lymphomas can spontaneously arise, we have found that CD40 stimulation can prevent the occurrence of this human lymphoma in mice. However, normal human B cell engraftment and function was not adversely affected in these mice by CD40 stimulation. This indicates that CD40 stimulation is selective in its effects on aggressive histology B cell lymphomas. Thus, CD40 stimulation either by antibody or a recombinant soluble ligand, may be of potential clinical use, not only in the treatment of EBV-induced B cell lymphomas, but also in their prevention.

Chemokine-induced human lymphocyte infiltration and engraftment in huPBL-SCID mice

Abstract: Publisher Summary The huPBL-SCID chimera model allows the examination of the effects of various chemokines using human cells and reagents in an in vivo setting. However, there are significant limitations to this model that are due to the uncharacterized effects of placing human lymphocytes in a xenogeneic environment. The original finding of Mosier and colleagues indicated that huPBLs engrafted only after intraperitoneal but not subcutaneous or intravenous injection into SCID recipients. These results have been confirmed by other laboratories. In addition, the number of huPBLs injected was critical for engraftment as well as the time of huPBL transfer, and the techniques used to assess human cell engraftment also add to the complexities of the model and of interpreting data. More than one technique is used to measure the extent of human cell engraftment, including polymerase chain reaction (PCR) detection of human-specific mRNA sequences, flow cytometric and immunohistological analysis using antibodies directed against human-specific markers, and quantitation of human immunoglobulin in mouse serum. Although PCR is the most sensitive method to qualitatively detect the presence of human cells, it does not permit the precise quantitation of human cell engraftment or trafficking.