SEARCH · PubMed Health

Results for “SCID mouse”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 307 records · Page 17Linked to original sources

PubMed1991

Human T cells in the SCID-hu mouse are phenotypically normal and functionally competent.

SCID-hu mice are heterochimeric animals that are constructed by transplanting human fetal thymus (Thy), liver (Liv), and/or lymph nodes into congenitally immunodeficient C.B-17 scid/scid (SCID) mice. Sensitive and specific two-color flow cytometric assays were used to evaluate human lymphocytes from peripheral blood of SCID-hu mice. Kinetic studies presented in this report show long term T lymphopoiesis in SCID-hu mice. Approximately one-half of SCID-hu mice constructed with Thy and Liv tissue develop detectable levels of circulating human T cells by 4 mo after transplantation. The average level of circulating human cells in SCID-hu mice is generally less than 2% of the total lymphoid cells in the peripheral blood of these mice. Some SCID-hu mice with as high as 13% human lymphocytes, however, have been detected. Nearly all human cells in the peripheral blood of SCID-hu mice are CD3+ cells that express TCR-alpha beta. The percentages of gamma delta+, CD4+, CD8+, CD25+, CD69+, and Leu-8+ cells among CD45+ cells in SCID-hu blood are similar to the levels found in adult peripheral blood. On average, 74% of SCID-hu T cells express CD45RA and 18% express CD29. Functional studies demonstrate that cells from SCID-hu Thy/Liv grafts or human T cells from SCID-hu peripheral blood are functionally competent to respond to mitogens or allogeneic human cells in vitro. They are similar to fetal thymocytes or adult T cells, respectively, in these responses. These studies demonstrate that the SCID-hu mouse is a useful model for the analysis of human immune differentiation and function in vivo.

Animals↗

PubMed1991

Recapitulation of normal and abnormal BB rat immune system development in scid mouse/rat lymphohemopoietic chimeras.

Mice homozygous for the mutation "severe combined immune deficiency" (C.B17-scid/scid) lack functional T and B lymphocytes and readily accept tumor xenografts. Partial lymphohemopoietic scid/human and mouse/rat chimeras have been described, but complete chimerization with thymic engraftment and generation of donor-origin thymocytes has not been achieved. We now report that low-dose irradiation permits the engraftment of BB rat fetal liver stem cells in scid recipients. We observed that BB rat fetal liver cells injected into irradiated scid mice establish a rat hemopoietic system in the scid mouse bone marrow and populate the scid mouse thymus. These stem cells generated rat-origin thymocytes that migrated to the scid mouse spleen, a peripheral lymphoid organ. Finally, we found that xenogeneic chimeras created using fetal liver cells from the abnormal (lymphopenic, diabetes prone) subline of BB rats recapitulated both the quantitative and phenotypic abnormalities of the donor rat. Xenogeneic lymphohemopoietic chimeras established in scid mice may provide a powerful new tool in the study of immune system development and autoimmunity.

Animals↗

PubMed1992

Growth and dissemination of human malignant melanoma cells in mice with severe combined immune deficiency.

BACKGROUND: The severe combined immune deficiency (SCID) mouse is lacking mature B and T lymphocytes and may be permissive for human tumor growth and metastasis. EXPERIMENTAL DESIGN: SCID mice received human melanoma cells of diverse origins including: 2 established cell lines, 4 early passage cell lines, and fresh or cryopreserved cells obtained directly from 9 patient biopsies. They were introduced into SCID mice via intraperitoneal, subcutaneous and intravenous injections. RESULTS: Tumor growth occurred with each of the 15 melanoma specimens for a take rate of 100% considering cell source. In addition, 60% of the 102 total mice injected displayed tumor growth in at least one site. The most consistent tumor growth (77%) occurred after intraperitoneal injection. Tumors developed in 41 and 48% of mice injected subcutaneously and intravenously, respectively. The mice developed both local tumor growth with palpable tumor nodules at injection sites and hematogenous and/or lymphatic dissemination to multiple sites in the abdominal and thoracic cavities. The number of metastases per animal averaged 16.3 and the number per organ ranged from 1 to 38. Melanotic and amelanotic tumor nodules obtained from a single patient retained their original characteristics with regard to melanin production after passage in the SCID mouse. The appearance of the human melanoma cells in SCID mouse tissues ranged from implants on the organ capsule to frank parenchymal organ involvement and vascular invasion. Some small foci of tumor were only detected using immunohistochemistry with monoclonal antibodies against the S-100 and HMB-45 to melanoma-related antigens. CONCLUSIONS: We conclude that the SCID mouse consistently supports growth, invasion, and metastatic spread of human melanoma cells, including specimens obtained from fresh patient biopsies. The SCID mouse will serve as a relevant in vivo model for studying the biology of human malignant melanoma and screening new therapeutic agents.

Animals↗

PubMed2004

[Human peripheral blood CD4+ T-lymphocytes reconstituting severe combined immunodeficient mouse-human cell immune system and its immunological function].

OBJECTIVE: To observe whether severe combined immunodeficiency disease (SCID) mice can reconstitute human cell immune system by adoptive transferring of human peripheral blood CD4+ T-lymphocytes to the peritoneal cavity in SCID mice, and to determine the characteristics and function of SCID mice immune system after the reconstitution. METHODS: SCID mice were injected mature human CD4+ T-lymphocytes to the peritoneal cavity, accompanied with the stimulation of rIL-2 after the injection. Six weeks after the injection, mice were killed in batch, the form and dimension of liver and spleen were observed. The DNA of human lymphocytes was detected in SCID mouse peripheral blood by PCR amplification. The lymphocytes phenotype of SCID mouse immune organs were assayed with immunohistochemistry. The concentration of human cytokines in SCID mouse blood serum was assayed with ELISA after transplanting xenografts. RESULTS: Intraperitoneal injection of SCID mice with mature human peripheral blood CD4+ T lymphocytes could graft human cell immune system to SCID mice. Human CD4+ T lymphocytes were found in the liver and spleen, and the immunological function of lymphocytes was normal. The HLA-II constant region segment of human lymphocytes was found in hu-CD4+ T-SCID mouse peripheral blood by PCR amplification. Human IL-2, TNF-alpha, and INF-gamma were found in the serum of hu-CD4+ T-SCID mice. CONCLUSION: Intraperitoneal injection of SCID mice with mature human peripheral blood CD4+ T lymphocytes can result in a human cell immune system. The method is simple, quick and has abundant donors.

Animals↗

PubMed1996

Phenotype and function of hematopoietic-derived cells in the CNS of SCID mouse-Lewis rat bone marrow chimeras.

Severe combined immunodeficient (SCID) mice previously transplanted with Lewis rat hematopoietic cells (SCID mouse-Lewis rat chimeras) developed experimental autoimmune encephalomyelitis (EAE) following injection with myelin basic protein (BP)-specific Lewis rat T lymphocytes. Rat T cells did not cause EAE in non-chimeric SCID mice. Thus, in addition to BP-specific rat T cells, transplanted rat hematopoietic cells were involved in the development of EAE in SCID mice. In order to examine the role of hematopoietic rat cells in the development of EAE, chimeras were constructed in SCID mice by transplanting 40 x 10(6) T cell-depleted adult Lewis rat bone marrow cells. Single cell suspensions of brain, blood and spleen from chimeric mice were phenotyped by monoclonal antibody staining specific for mouse or rat cellular differentiation markers at 2 week intervals. Brain cells from chimeric mice were also evaluated for the presence of rat antigen-presenting cells (APC). Four and six weeks after hematopoietic cell transfer, mouse brain contained rat cells expressing the phenotypic markers (CD45+, CD11b/c+) of CNS antigen-presenting cells (APC). Six weeks after hematopoietic cell transfer, rat cells populating the CNS of chimeras were shown to function as APC, stimulating BP-specific Lewis rat T lymphocytes in vitro.

Animals↗

PubMed1994

SCID-Hu mouse as a model for human lung HIV-1 infection.

HIV induces a multi-organ infection with a dual tropism for both lymphocytes and monocytes/macrophages. The lung is a target both for HIV infection and HIV-related opportunistic infections. The SCID mouse has provided the opportunity to develop a small animal model for HIV infection. However, HIV-1 infection of the human fetal thymus and liver (SCID Liv/Thy) implanted in these mice occurred only after direct intraimplant injection of HIV-1 and the resultant HIV-1 infection was restricted to the human thymus. Here we report that human foetal lung can develop in SCID Liv/Thy mice resulting in the development of normal human alveolar and bronchiolar lung compartments which can be productively infected with cell-free HIV-1 virus, leading to a systemic and bifocal infection. This SCID-Hu model should be useful for studying AIDS physiopathology, human viruses with lung tropism and for helping to define gene therapy protocols in lung human cells in vivo.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Hepatitis C virus viremia in SCID-->BNX mouse chimera.

Chimpanzees are currently the only nonhuman animal model for reproducible propagation of hepatitis C virus (HCV). A chimeric mouse model was used for the induction of hepatitis C viremia, using BNX (beige/nude/X-linked immunodeficient) mice preconditioned by total body irradiation and reconstituted with SCID mouse bone marrow cells. HCV-infected liver fragments from patients with HCV RNA-positive sera were transplanted under the kidney capsule of the chimeric mice. HCV-specific RNA sequences were detected by reverse transcriptase nested polymerase chain reaction (RT-PCR) in serum of approximately 50% of grafted animals. In addition, normal liver specimens were incubated with HCV serum and transplanted into chimeric mice, leading to viremia in approximately 25% of animals. Sequential histologic evaluation of the liver implants, from day 2 to week 14 after transplantation, revealed loss of lobular architecture within the implants. However, viremia persisted for 10-50 days after transplantation. These results offer a new HCV model.

Animals↗

PubMed2001

Predictive efficacy of SCID-hu mouse models for treatment of human cytomegalovirus infections.

There are few animal models to evaluate the in vivo activity of new compounds against human cytomegalovirus (HCMV) infections, as virus replication is largely limited to human cells. In our studies, we have utilized SCID mice implanted with human tissue (SCID-hu) and inoculated with HCMV as models for infections of the eye or visceral organs in an immunocompromised host. For the ocular model, fetal human retinal tissue was implanted in the anterior chamber of the SCID mouse eye and inoculated 6-9 weeks later with 2,000-7,500 plaque-forming units (pfu) of HCMV. In the second model, fetal thymus and liver (thy/liv) tissue was implanted under the kidney capsule of SCID mice and inoculated 12-14weeks later with 2,200-9,000 pfu of HCMV. At various times after infection, implant tissues were removed, homogenized, and HCMV titres quantified by plaque assay. The replication of the Toledo strain of HCMV in both models was similar in that viral titres increased through day 21, remained high through day 35, and then gradually decreased. To validate the two models, the efficacy of ganciclovir (GCV) and cidofovir (CDV) was determined in both ocular and thy/liv model implants. In SCID-hu retinal tissue, once daily intraperitoneal (i.p.) treatment with 33 mg GCV per kg significantly reduced viral titres (2-20-fold) between 14 and 28 days after infection. In SCID-hu thy/liv implants, the same treatment regimen reduced viral replication either completely or by 3-5 log10. In retinal implant tissue, i.p. treatment with 25 mg CDV per kg once daily for 14 days, followed by three times weekly for the next 14 days, reduced viral titres by 2-3 log10 between 10 and 42 days after infection. In comparison, once daily i.p. administration of 30 mg CDV per kg completely inhibited HCMV replication in thy/liv implants. These results indicate that both the SCID-hu retinal and SCID-hu thy/liv implant models are useful for determining in vivo activity against HCMV, and appear to be predictive of efficacy for both ocular and systemic infections in humans.

Animals↗

PubMed1992

Growth of Hodgkin cell lines in severely combined immunodeficient mice.

No animal model exists for the in vivo growth of Hodgkin's-lymphoma-derived cells. Neither unmanipulated Hodgkin's-disease(HD)-derived cell lines nor primary biopsy tissue could be grown in nude mice. Since the severe combined immunodeficient (SCID) mouse has been reported to be a better recipient for transplanted human lymphatic tissue than the nude mouse, we tested whether SCID mice provide suitable conditions for the in vivo growth of HD cell lines. Tumorigenicity of HD cells was tested in untreated and pre-treated SCID mice and in another combined immunodeficient mouse strain, beige/nude/X-linked immunodeficient (BNX) mouse. SCID mice supported in vivo growth of the 6 HD cell lines tested (L428, L540, L591, DEV, HD-LM2, KM-H2). Only one of the 6 lines (DEV) was tumorigenic in BNX mice. No HD cell line proliferated in T-cell-deficient nude mice. Thus, in vivo growth of HD cell lines appeared to be related to the degree of host immunodeficiency. Additional growth supportive treatments such as fibrosarcoma co-transplantation, intraperitoneal mineral oil injection or immunosuppressive pre-treatment (anti-asialo-GMI-antibody injection) permitted growth of 3 additional HD cell lines in BNX mice. The immunophenotype and karyotype of explanted graft cells were identical to the original cell lines. Our experiments describe an effective and reproducible xenograft model for growth of Hodgkin's-disease-derived cell lines. This may be of value for elucidating the growth characteristics of Hodgkin's-lymphoma-derived cells as well as for testing new therapeutic regimens.

Animals↗

PubMed1991

Preclinical evaluation of human hematolymphoid function in the SCID-hu mouse.

Work in the SCID-hu system has progressed significantly over the past 3-4 years. Reliable SCID-hu constructs can now be created for the evaluation of long-term multilineage human hematopoiesis, human immune function, and HIV infection of human hematolymphoid organs in vivo. Given these constructs, a variety of therapeutically important modalities can now be discovered and developed with a relevant in vivo model, prior to the time that they are moved into the clinic. With further progress in this and other preclinical models, useful therapies for important human disease states will hopefully be forthcoming at an even faster pace.

Acquired Immunodeficiency Syndrome↗

PubMed1987

Correlation of T cell receptor gene rearrangements to T cell surface antigen expression and to serum immunoglobulin level in scid mice.

The severe combined immunodeficient (scid) mouse which has undetectable serum immunoglobulin (Ig) contains a small number of thymic lymphocytes which express Thy-1 and IL2 receptors (IL2R) but not Lyt-2 or L3T4 molecules. These thymocytes did not show any rearrangement of T cell receptor (TCR) beta-chain genes. Such thymocyte characteristics in the scid mouse were similar to the 15-day embryonic thymocytes in ordinary mice, indicating that the scid mouse thymocytes are arrested in the early stage of intrathymic differentiation. However, low or medium level serum Ig was occasionally found in the littermates of the scid mouse. The thymocytes of these mice showed some evidence of TCR beta-chain gene rearrangement and the presence of Lyt-2+/L3T4+ cells in correlation with the serum Ig level. In the mice with some serum Ig the thymocyte cell number was increased and the proportion of IL2R+ cells was decreased. Collectively, these results suggest that the rearrangement of TCR beta-chain genes is associated with the expression of Lyt-2 and L3T4 molecules in intrathymic differentiation and probably with cell proliferation of the migrated lymphoid cells in the scid mouse.

Animals↗

PubMed1994

Human RANTES induces the migration of human T lymphocytes into the peripheral tissues of mice with severe combined immune deficiency.

The human cytokine, Recombinant Human Regulated on Activation, Normal T Expressed and Secreted (rhRANTES), is a small glycoprotein secreted by activated T cells and platelets and is structurally related to a family of chemotactic cytokines called chemokines. Evaluation of the effects of chemokines on human cells has largely been limited to in vitro binding assays. In an effort to study the in vivo effects of chemokines on human leukocyte migration, we examined the ability of rhRANTES to induce human T cell infiltration using a human/severe combined immune deficient (SCID) mouse model. SCID mice received human peripheral blood lymphocytes, followed by sequential subcutaneous injections of rhRANTES in the hind flank for 3 days. The skin and underlying tissue from the rhRANTES injection site were then biopsied and examined for the extent of human mononuclear cell infiltration. rhRANTES induced significant mononuclear cell accumulation 72 h after injection. Immunohistological evaluation determined that the majority of the cells recruited in response to rhRANTES injections were human CD3+ T cells with equal numbers of CD4+ and CD8+ cells. In contrast, subcutaneous injections of recombinant human macrophage colony-stimulating factors resulted in little human cellular infiltration. Murine mononuclear cell infiltration in response to rhRANTES was also present suggesting that the in vivo effects of rhRANTES may be both direct and indirect. These results demonstrate that rhRANTES induces significant human T cell migration in vivo and suggests that the human/SCID mouse model may provide an important tool in studying the in vivo effects of chemokines on human leukocytes and leukocyte subsets.

Animals↗

PubMed2001

Study on the role of G1 cyclins in Epstein-Barr virus-associated human lymphomas maintained in severe combined immune deficiency (SCID) mice.

Five Epstein-Barr virus (EBV)-positive human lymphoma cell lines maintained in severe combined immune deficiency (SCID) mice were used to investigate the role of G1 cyclins in EBV-induced lymphomagenesis. All the primary tumors had been negative for EBV but became positive after establishment in SCID mice, with monoclonal immunoglobulin gene rearrangement and EBV monoclonality. To compare the expression status of G1 cyclins, these EBV-associated lymphoma lines (6 EBV[-] human SCID mouse lymphoma lines, 13 human B cell lymphomas and 8 samples of human tonsil tissue) were examined by reverse transcription-polymerase chain reaction-Southern blotting, Western blotting and immunohistochemistry. mRNA expression of cyclin D1 (CCND1), cyclin D2 (CCND2), cyclin E (CCNE), cyclin-dependent kinase 2 (CDK2) and 4 (CDK4) was found in all 3 types of lymphomas. Western blotting demonstrated identical results. Immunohistochemistry revealed CCND1 to be negative in all lymphomas. CCND2 was positive and restricted to the nuclei in all EBV(+) SCID mouse lymphoma lines, whereas it was limited to the cytoplasm in half of the EBV(-) counterparts. CCNE was positive in the nuclei in all EBV(+) but negative in all EBV(-) SCID mouse lymphoma lines. Immunoprecipitation of EBV(+) and (-) SCID mouse lymphomas for CCND1, CCND2 and CCNE vs. p21, PCNA and CDK2 or CDK4 demonstrated that, in EBV(+) SCID lines, CCND2/CDK4 complexes were present without binding to p21, suggesting independence from p21 regulation. In EBV(-) SCID mouse lymphomas, half of the cases showed complex formation of CCND2/CDK4 without binding of p21. In contrast, CCND1/CDK4 and CCNE/CDK2 were under regulation of p21 in both EBV(+) and (-) lymphomas. These results suggest that differential expression of CCNDs, CCNE and CDKs, as well as variation in their subcellular localization and association with CDK-inhibitor protein, could explain differences in cell proliferation between EBV(+) and EBV(-) lymphomas.

Animals↗

PubMed1999

Expression of growth regulatory genes in a SCID mouse-human model of intestinal epithelial regeneration.

Analysis of human intestinal epithelial regeneration has been limited. This study has used a novel SCID mouse-human model to test the hypothesis that distinct stages of human intestinal epithelial regeneration are accompanied by differential expression of growth regulatory genes. Disaggregated epithelium, which included crypt cell aggregates, was isolated from human fetal small intestine and transplanted subcutaneously in SCID mice. This method induced a coordinated regeneration response and enabled temporal separation of cell populations at different stages of histogenesis and cytodifferentiation. Graft epithelium was identified using a specific anti-human monoclonal antibody (MAb 5D3) against cytokeratins 8 and 18. Functional epithelial lineages were identified by appropriate markers. Growth regulatory genes relevant to proliferation and apoptosis, including Bcl-2, p53 and Ki67, were assayed at different stages of regeneration. During early regeneration, Bcl-2, p53, and Ki67 were expressed throughout the epithelial compartment. On completion of regeneration, these genes were expressed only in crypt epithelium and were absent from villi. This study has established a novel SCID mouse-human model of intestinal epithelial regeneration. During early regeneration, increased Bcl-2 and Ki67 expression may indicate suppression of apoptosis and enhanced proliferation respectively, consistent with expansion of the stem cell fraction. The p53 gene may influence pathways of differentiation during regeneration, analogous to its role during development.

Animals↗

PubMedDate not supplied

Cytokines delivered by biodegradable microspheres promote effective suppression of human tumors by human peripheral blood lymphocytes in the SCID-Winn model.

A new technology for the local and sustained delivery of immunostimulatory molecules to the tumor environment for cancer immunotherapy was evaluated. The ability of cytokines delivered by biodegradable microspheres to promote the antitumor activity of human peripheral blood lymphocytes (PBL) was tested in a human PBL, human tumor, and SCID mouse (SCID-Winn) model. Co-engraftment of human recombinant IL-12-loaded microspheres with human PBL and tumors in SCID mice promoted complete tumor suppression in as many as 100% of the mice, whereas microspheres loaded with polyethyleneglycol-interleukin-2 suppressed but did not eliminate the growth of tumor xenografts. Control microspheres (loaded with bovine serum albumin) in the presence of human PBL or cytokine-loaded microspheres in the absence of human PBL had no tumor-suppressive effect. Coincident with the enhancement of the human PBL-mediated antitumor activity in mice treated with IL-12-loaded microspheres was the production and release of human IFN-gamma indicating that IL-12 released from the microspheres results in the activation of the engrafted human PBL. The results establish that biodegradable microspheres represent an effective tool for the local and sustained delivery of cytokines to the tumor environment for cancer immunotherapy.

Adjuvants, Immunologic↗

PubMed2000

Antibody targeting of doxorubicin-loaded liposomes suppresses the growth and metastatic spread of established human lung tumor xenografts in severe combined immunodeficient mice.

Beta1 integrins, expressed on the cell surface of human non-small cell lung carcinomas, are used here as a target for the selective delivery of anti-cancer drug-loaded liposomes. Fab' fragments of a monoclonal antibody specific for human beta1 integrins were conjugated to sterically stabilized liposomes. Confocal microscopy of beta1 integrin-positive lung tumor cells incubated with fluorescently labeled anti-beta1 Fab immunoliposomes revealed a tumor-specific binding and efficient internalization of the liposomes into the tumor cells. The ability of these liposomes to deliver cytotoxic drugs to the tumor and kill these cells was demonstrated in vitro by incubating tumor cells with doxorubicin-loaded anti-beta1 Fab' immunoliposomes. The drug-loaded immunoliposomes were >30-fold more cytotoxic to the tumor cells than drug-loaded liposomes without antibody, nonspecific Fab' control immunoliposomes with drug or immunoliposomes without drug. The therapeutic efficacy of doxorubicin-loaded immunoliposomes was also evaluated in a metastatic human lung tumor xenograft/severe combined immunodeficient (SCID) mouse model. SCID mice that received i.v. injections of human lung tumor cells developed primary tumor nodules in the lung that subsequently metastasized to the liver and adrenal gland. Treatment of SCID mice bearing established lung tumor xenografts with doxorubicin-loaded anti-beta1 Fab immunoliposomes resulted in a significant suppression of tumor growth (monitored periodically by quantifying serum levels of a tumor marker), whereas tumors grew progressively in mice treated with control formulations. In addition to suppressing the growth of the primary lung tumor nodules, the immunoliposomes prevented the metastatic spread of the tumor to the liver and adrenal glands and increased the median survival time of the tumor-bearing mice. We conclude that Fab' immunoliposomes directed to tumor-associated integrins represent a potentially viable approach clinically for the selective delivery of drugs to solid tumors and may be useful in preventing the metastatic spread of lung cancer.

Adrenal Gland Neoplasms↗

PubMed1996

Human interferon-inducible protein-10 induces mononuclear cell infiltration in mice and promotes the migration of human T lymphocytes into the peripheral tissues and human peripheral blood lymphocytes-SCID mice.

The human cytokine, interferon-inducible protein-10 (IP-10), is a small glycoprotein secreted by activated monocytes, T cells, keratinocytes, astrocytes, and endothelial cells and is structurally related to the alpha subfamily of chemotactic cytokines called chemokines (Taub and Oppenheim, Cytokine 5:175, 1993). However, in contrast to other alpha chemokines that induce neutrophil migration, IP-10 has been shown to chemoattract monocytes and T lymphocytes in vitro, suggesting a role in T-cell-mediated immune responses. We therefore examined the effects of human IP-10 after in vivo administration. IP-10 induces significant mononuclear cell infiltration after subcutaneous injections in normal mice. In an effort to study the in vivo effects of IP-10 on human leukocyte migration, we then examined the ability of recombinant human IP-10 (rhIP-10) to induce human-T-cell infiltration using a human/severe combined immune deficiency (SCID) mouse model. SCID mice received an intraperitoneal injection of human peripheral blood lymphocytes (10(8) cells), followed by a subcutaneous injection of rhIP-10 (1 micrograms/injection) in the hind flank for 4 hours or sequential injections for 3 days. The skin and underlying tissue from the rhIP-10 injection site were then biopsied and examined for the extent of mononuclear cell infiltration. rhIP-10 again induced significant mononuclear cell accumulation 72 hours after injection. Immunohistologic evaluation determined that a significant number of human CD3+ T cells were recruited in response to rhIP-10 injections. These results show that rhIP-10 is capable of inducing human T-cell migration in vivo and may play an important role in monocyte and lymphocyte recruitment into inflammatory sites.

Animals↗

PubMed2004

Combination immunotherapy of B-cell non-Hodgkin's lymphoma with rituximab and interleukin-2: a preclinical and phase I study.

PURPOSE: Cytokine-induced modulation of innate immunity is being explored to enhance the activity of monoclonal antibodies. Severe combined immunodeficient (SCID) mice engrafted with peripheral blood leukocytes (PBLs) from Epstein Barr virus-seropositive donors develop human B-cell non-Hodgkin's lymphomas [B-NHLs (hu-PBL-SCID mouse model)]. We used this hu-PBL-SCID mouse model to study the synergism between interleukin (IL)-2 and rituximab. We also conducted a phase I trial of IL-2 and rituximab in relapsed B-NHL to study whether expansion of natural killer (NK) cells and enhanced cellular cytotoxicity could be safely accomplished in vivo. EXPERIMENTAL DESIGN: Hu-PBL-SCID mice were treated with various schedules of rituximab and IL-2, with survival as the end point. Patients with relapsed B-NHL received rituximab (375 mg/m2 weekly x 4) followed by daily low-dose IL-2 (1 MIU/m2/day x 4 weeks) with pulses of intermediate-dose IL-2 (3-15 MIU/m2). Toxicity, NK cell numbers, and cellular cytotoxicity were measured. RESULTS: In the hu-PBL-SCID mouse, the combination of rituximab and IL-2 showed greater activity against B-NHL than either agent alone. Treatment was most effective when IL-2 was given before rituximab. Twelve patients with heavily pretreated B-NHL entered the phase I trial. Toxicity was manageable, and responses were observed. NK cell expansion and enhanced cellular cytotoxicity against a B-cell lymphoma target were observed but did not correlate with response. CONCLUSIONS: The combination of IL-2 and rituximab is synergistic against B-NHL in the hu-PBL-SCID model. In the phase I trial, a sequential combination of rituximab and IL-2 was well tolerated and achieved biological end points. Responses were observed.

Adult↗