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PubMed2000

Human amniotic epithelial cells are promising transgene carriers for allogeneic cell transplantation into liver.

As human amniotic epithelial tissue is formed on about the eighth day after fertilization, human amniotic epithelial cells (hAEC) may have multipotency to differentiate into various organs, such as brain, heart, or liver. In this study, we showed evidence of the synthesis and excretion of albumin by hAEC, by immunostaining and enzyme-linked immunoassay. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot analyses revealed the expression of albumin mRNA and protein, respectively. In addition, hAEC also demonstrated immunoreactivity to genetic markers of liver lineage, such as human serum albumin and alpha-fetoprotein. Transplanted hAEC to Scid mouse liver showed positive immunoreactivity to albumin and alpha-fetoprotein. Genetically modified cells containing the beta-galactosidase (LacZ) gene (AxCALacZ) were integrated in liver parenchyma. Human polymorphic gene analysis in Scid mouse liver after the implantation of hAEC showed that these Scid mouse livers obviously contained this human-specific gene until day 7 after the cell transplantation. As hAEC do not cause any acute rejection by allotransplantation, we conclude that hAEC may be useful as a transgene carrier to treat patients with inherited liver diseases.

Albumins↗

PubMed1991

Gastrointestinal candidiasis in a murine model of severe combined immunodeficiency syndrome.

A murine model of severe combined immunodeficiency syndrome (scid mice) affords an opportunity to study the interaction of Candida albicans with a host lacking functional B- and T-cell mechanisms. We have previously reported no significant difference in yeast recovery after intravenous challenge of BALB/c mice and scid mice with C. albicans (S. Mahanty, R.A. Greenfield, W.A. Joyce, and P.W. Kincade, Infect. Immun. 56:3162-3166, 1988). In this study, we evaluate the course of gastrointestinal candidiasis after a single oral challenge with C. albicans. BALB/c and scid mice received H2O containing 10(6) C. albicans per ml for 16 h. Half the mice of each strain continuously received H2O containing 1 mg of tetracycline per ml. Stool samples were cultured for yeast twice weekly until they were negative three consecutive times or positive for 8 weeks. Mice were then sacrificed for quantitative cultures of liver, spleen, and kidneys. At eight weeks postinoculation, 2 of 13 BALB/c mice, 0 of 14 BALB/c mice receiving tetracycline, 6 of 12 scid mice, and 8 of 13 scid mice receiving tetracycline had positive stool cultures (P less than 0.05, likelihood ratio chi-square). Quantitative recovery of yeasts from stools was also higher in the scid mice. Cultures of liver, spleen, and kidneys wer negative in all BALB/c mice and essentially all negative in scid mice; a single colony was isolated from the kidney of one scid mouse and the liver of another scid mouse. We conclude that B cells and/or T cells and their products are important in gastrointestinal colonization with C. albicans but that even in their absence, dissemination of infection from the gastrointestinal tract does not consistently occur. Thus, other aspects of host defense must be critical in containing gastrointestinal Candida colonization.

Administration, Oral↗

PubMed1994

Conserved sequence homology of cysteine-rich regions in genes encoding glycoprotein A in Pneumocystis carinii derived from different host species.

Pneumocystis carinii surface glycoprotein A (gpA) exhibits host species-specific phenotypic and genotypic variation. Despite this heterogeneity, the gpAs of P. carinii isolated from different host species appear to be homologous molecules sharing certain biochemical and antigenic characteristics. Using two degenerate oligodeoxyribonucleotide primers corresponding to conserved cysteine regions from ferret and rat P. carinii gpAs, a PCR product of approximately 300 bp was amplified from ferret, rat, and SCID mouse P. carinii-infected lung genomic DNA. Northern (RNA) hybridization revealed a transcript of 3,450 nucleotides in P. carinii-infected SCID mouse lung mRNA, which is similar in size to the transcripts for ferret and rat P. carinii gpAs. Nucleotide sequence analysis of SCID mouse P. carinii gpA subclones derived from the PCR products identified two isoforms, which were 89% identical to each other in the amplified region and 73 and 54% identical to the rat- and ferret-derived P. carinii gpA genes, respectively. Comparison of the deduced amino acid sequences of mouse, ferret, and rat P. carinii gpAs revealed striking similarity in residues adjacent to and including the conserved cysteines. Furthermore, the spacing of two proline residues is invariant, and a potential N-linked glycosylation site is found at a similar position in all of the gpAs. Despite the heterogeneity observed in P. carinii gpAs, the conservation of cysteine residues and adjacent sequences implies similar secondary structure and, most likely, similar function for the gpAs of P. carinii isolated from different host species.

Amino Acid Sequence↗

PubMed1996

Measles virus infection of thymic epithelium in the SCID-hu mouse leads to thymocyte apoptosis.

Mortality from measles is caused mostly by secondary infections associated with the depression of cellular immunity. The mechanism of immune suppression and the role of virus strain differences on the immune system are incompletely understood. SCID-hu mice were used to determine the effects of virulent, wild-type (Chicago-1) and avirulent, vaccine (Moraten) strains of measles virus (MV) on the human thymus in vivo. Chicago-1 replicated rapidly, with a 100-fold decrease in numbers of thymocytes, whereas Moraten replicated slowly, without significant thymocyte death. Productive MV infection occurred not in thymocytes but in thymic epithelial and myelomonocytic cells. Wild-type MV infection of thymic stromata leads to induction of thymocyte apoptosis and may contribute to a long-term alteration of immune responses. The extent of thymic disruption reflects the virulence of the virus, and therefore the SCID-hu mouse may serve as the first small animal model for the study of MV pathogenesis.

Animals↗

PubMed2000

Human peripheral blood lymphocyte severe combined immunodeficiency (hu-PBL SCID) models of toxoplasmosis.

Toxoplasmosis is a potentially fatal opportunistic infection of immunocompromised hosts. Improved animal models of toxoplasmosis are needed to more nearly approximate conditions that occur in immunocompromised humans. The development of models of toxoplasmosis using human peripheral blood lymphocytes (hu-PBL) transplanted into severe combined immunodeficiency (SCID) mice is described here. Transplantation of hu-PBL into SCID mice without prior conditioning of the mice resulted in detectable differences in quantitative histological scores of brain inflammation due to Toxoplasma gondii infection, but did not alter mortality when compared to SCID mouse controls. The lack of detectable differences in survival were due to inadequate engraftment of hu-PBL, as assessed by flow cytometry. Unconditioned hu-PBL SCID mice had low titre T. gondii-specific antibody detectable after infection. When pretransplantation conditioning with irradiation and antiasialo GM 1 (n-glucolyl neuraminic acid) antibody was used, prolonged hu-PBL engraftment was observed in SCID mice, which was associated with worsened histopathology and usually impaired survival when compared with SCID mouse controls. When pretransplantation conditioning with irradiation, antiasialo GM antibody and polyethylene glycol-conjugated IL-2 was used, prolonged hu-PBL engraftment was also documented, but this did not affect survival from T. gondii infection when compared with similarly conditioned SCID mouse controls. The latter conditioning protocol resulted in hu-PBL SCID mice producing high titre T. gondii-specific antibody after infection. Conditioned hu-PBL SCID mice had evidence of increased T. gondii-induced inflammatory scores when compared with conditioned SCID mice. These models show promise for the study of the pathogenesis of toxoplasmosis and conditioned hu-PBL SCID mice may have applications for the evaluation of novel therapies for toxoplasmosis in immunocompromised humans.

Acute Disease↗

PubMed1995

Lymphomagenesis in the SCID-hu mouse involves abundant production of human interleukin-10.

Both human (hu) and viral (v) interleukin-10 (IL-10) appear to be important cofactors in the survival and growth of lymphoblastoid cell lines infected with Epstein-Barr virus (EBV). When mice with severe combined immune deficiency (SCID) are injected with human peripheral blood lymphocytes (PBL) from normal individuals who are seropositive for EBV, the majority of hu-PBL-SCID mice will develop an EBV-associated lymphoproliferative disease (EBV-LPD) of human B-cell origin, not unlike some cases of EBV-LPD that are seen in immunocompromised individuals. The role of huIL-10 or vIL-10 in this chimeric mouse model of EBV-LPD is unknown. In the present study, we show that hu-PBL-SCID mice that develop EBV-LPD have significant elevation of serum huIL-10 levels compared with mice that do not develop EBV-LPD (P = .005). vIL-10 was undetectable in all animals. The EBV+ tumor samples express transcript for huIL-10 and huIL-10 receptor, express huIL-10 protein by immunohistochemical staining, and show specific binding of recombinant (r) huIL-10. In vitro analysis of the functional consequences of rhuIL-10 binding to IL-10 receptors on fresh EBV+ tumor cells shows that rhuIL-10 can prevent programmed cell death as well as promote proliferation and can do so at concentrations of huIL-10 found in vivo. Thus, huIL-10 production by EBV+ tumor cells may contribute directly to their malignant outgrowth in the hu-PBL-SCID mouse by two autocrine mechanisms: prevention of programmed cell death and proliferation. The implications of such findings with regard to EBV-LPD in humans is discussed.

Animals↗

PubMed1993

Conditions required for myelopoiesis in murine spleen.

While the spleen is an active site for myelopoiesis during the late embryonal and perinatal stages, the activity is gradually lost later. However, myelopoiesis in the adult spleen can be reactivated by irradiation or various stimulants. In this study we investigated factors which determine the myelopoiesis-supporting activity in the adult spleen. To address this question, we used scid mouse because virtually no lymphocytes, which might compete in the splenic microenvironment with hematopoietic progenitors, are present there. The results demonstrated: 1. Even in scid mouse, the myelopoiesis-supporting activity in the spleen is lost within a week after birth as in normal mice. 2. While myelopoiesis does not occur in the spleen of unstimulated scid mouse by bone marrow transfer alone, myelopoiesis in the spleen is reactivated by irradiation or lipopolysaccharide (LPS) application. 3. Myelopoiesis in the spleen induced by irradiation is dependent on c-kit and its ligand steel factor (SLF), because it was suppressed completely by the monoclonal antibody (mAb) against c-kit. 4. The expression of SLF transcripts in the spleen was enhanced after irradiation. These results suggest that the factor which determines myelopoietic activity in the spleen resides primarily in the status of the splenic microenvironment.

Animals↗

PubMed2000

Conditions that enable human hematopoietic stem cell engraftment in all NOD-SCID mice.

BACKGROUND: Transplantation of human hematopoietic stem cells is the only true test of their long-term repopulation potential. Models are readily available to evaluate murine hematopoietic stem cells, but few exist that allow reliable quantification of human stem cells. The non-obese diabetic-severe combined immunodeficient (NOD-SCID) mouse model enables quantification of human hematopoietic stem cells, but the conditions that permit human engraftment in all animals have yet to be defined. The aims of the project were, therefore, to describe the variables that allow human engraftment in the NOD-SCID mouse model and the techniques that accurately quantify this engraftment. METHODS: NOD-SCID mice that had or had not received 250, 325, or 400 cGy irradiation received cord blood (CB) mononuclear or CD34+ cells i.v. or i.p. Mice were killed 6 weeks after transplantation, and the bone marrow, spleen, and thymus were harvested. Four-color flow cytometric analysis, semi-quantitative PCR, myeloid and erythroid progenitor, and stem cell assays were used to monitor human engraftment. RESULTS: A 250 or 325 cGy and i.v. injection of CB mononuclear or CD34+ cells is required to detect multilineage human engraftment in the bone marrow, spleen, or thymus of NOD-SCID mice. Four-color flow cytometric analysis and semi-quantitative PCR enable accurate detection of 0.1% human cells. Progenitor and stem cell assays provide functional information about the engrafted cells. CONCLUSIONS: Successful development of the NOD-SCID mouse model and techniques to assess human engraftment now allow it to be used reliably to analyze the effects of short-term cytokine exposure on the long-term repopulating capacity of CB stem cells.

Animals↗

PubMed1999

Molecular analysis of the heavy chain of antibodies that recognize the capsular polysaccharide of Neisseria meningitidis in hu-PBMC reconstituted SCID mice and in the immunized human donor.

The severe combined immunodeficient (SCID) mouse model, engrafted with human peripheral blood mononuclear cells (hu-PBMC) has proven to be useful in studying the human immune response. A major limitation of the hu-PBMC-SCID model has been the failure to consistently demonstrate a primary human immune response. Previously we developed a hu-PBMC-SCID mouse model in which we addressed both issues of adequate human lymphocyte engraftment and impaired differentiation. We demonstrated that a primary human immune response to the T-independent (TI-2) meningococcal group C capsular polysaccharide (MCPS) can be obtained in hu-PBMC-SCID mice by the administration of human cytokines. In this study we compared the V(H) sequence of the MCPS response generated by B cells derived from a volunteer in the SCID mouse model to those generated by the donors' B cells in vivo. Human peripheral blood mononuclear cells were recovered from MCPS immunized hu-PBMC-SCID mice and immunized donor. B cells with specificity for MCPS were isolated from these cell preparations using an anti-idiotypic monoclonal antibody which mimics MCPS. Immunoglobulin mRNA was isolated from single cells, amplified by the polymerase chain reaction, cloned and sequenced. We analysed a total of 15 V(H) regions from B cells obtained from SCID mice and a total of 13 V(H) regions from B cells obtained from the immunized donor. The response differed between SCID and in vivo cells, when studied at the genetric level. V, D and J gene usage was markedly different, however canonical structures of the hypervariable loops were conserved. The complementary determining region 3 (CDR3) varied, such that SCID-derived sequences encoded longer CDR3 s than those of the donor. However all CDR3 s were rich in hydrophobic amino acids, most notably tyrosine and tryptophan, a characteristic common to many carbohydrate binding antibodies.

Amino Acid Sequence↗

PubMed2003

Differentiation of varicella-zoster virus ORF47 protein kinase and IE62 protein binding domains and their contributions to replication in human skin xenografts in the SCID-hu mouse.

To investigate the role of the ORF47 protein kinase of varicella-zoster virus (VZV), we constructed VZV recombinants with targeted mutations in conserved motifs of ORF47 and a truncated ORF47 and characterized these mutants for replication, phosphorylation, and protein-protein interactions in vitro and for infectivity in human skin xenografts in the SCID-hu mouse model in vivo. Previous experiments showed that ROka47S, a null mutant that makes no ORF47 protein, did not replicate in skin in vivo (J. F. Moffat, L. Zerboni, M. H. Sommer, T. C. Heineman, J. I. Cohen, H. Kaneshima, and A. M. Arvin, Proc. Natl. Acad. Sci. USA 95:11969-11974, 1998). The construction of VZV recombinants with targeted ORF47 mutations made it possible to assess the effects on VZV infection of human skin xenografts of selectively abolishing ORF47 protein kinase activity. ORF47 mutations that resulted in a C-terminal truncation or disrupted the DYS kinase motif eliminated ORF47 kinase activity and were associated with extensive nuclear retention of ORF47 and IE62 proteins in vitro. Disrupting ORF47 kinase function also resulted in a marked decrease in VZV replication and cutaneous lesion formation in skin xenografts in vivo. However, infectivity in vivo was not blocked completely as long as the capacity of ORF47 protein to bind IE62 protein was preserved, a function that we identified and mapped to the N-terminal domain of ORF47 protein. These experiments indicate that ORF47 kinase activity is of critical importance for VZV infection and cell-cell spread in human skin in vivo but suggest that it is the formation of complexes between ORF47 and IE62 proteins, both VZV tegument components, that constitutes the essential contribution of ORF47 protein to VZV replication in vivo.

Animals↗

PubMed2002

Molecular and immunological methods to detect rotavirus in formalin-fixed tissue.

In 1999, a tetravalent rhesus-based rotavirus vaccine was withdrawn from the market after reports of intussusception cases among vaccinated infants. Methods to detect rotavirus in formalin-fixed pathology specimens from such patients will be important in examining the possible associations between the vaccine and intussusception, in investigating fatalities caused by natural rotavirus infection, and in furthering our understanding of the pathogenesis of rotavirus disease. Three different methods, reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and in situ hybridization (ISH), were developed to detect rotavirus in infected cell lines that were fixed in formalin and embedded in paraffin. Using specific primer pairs to identify the VP4 gene with a one-step RT-PCR method, we detected simian rotavirus strains RRV and YK-1 in the liver of an RRV-infected SCID mouse and in the small intestine of an YK-1 infected macaque, respectively. Using a two-step indirect immunoalkaline phosphatase technique, we found RRV antigens in the liver of an infected SCID mouse with a rabbit polyclonal anti-group A rotavirus antibody and a murine monoclonal anti-rotavirus VP2 antibody. Using riboprobes designed to detect RRV genes, VP4 and NSP4, we obtained a positive hybridization signal in the same area of the infected SCID mouse liver as the area in which rotavirus antigens were localized. These techniques should prove valuable to detect rotavirus antigens and nucleic acids in tissues from patients infected naturally with rotavirus or with intussususception associated with rotavirus vaccine.

Animals↗

PubMed1999

Immunotherapy of human ovarian carcinoma with OvaRex MAb-B43.13 in a human-PBL-SCID/BG mouse model.

The monoclonal antibody (MAb) B43.13, binding to the ovarian cancer-associated antigen CA125, has been injected into more than 200 patients with ovarian cancer to detect recurrence of the disease. The follow-up of the patients revealed surprisingly long survival spans for several patients despite high CA125 levels. To investigate the therapeutic effectiveness of OvaRex MAb-B43.13 (AltaRex, Edmonton, Canada) under well-controlled conditions, the antibody was tested in a human-PBL-SCID/BG mouse model with CA125 positive human ovarian cancer cells. Mice were reconstituted with human peripheral blood lymphocytes (PBL, normal donors) by intraperitoneal (IP) injection of 2 to 3 x 10(7) PBL/mouse. OvaRex MAb-B43.13 was administered at 100 microg/mouse in phosphate buffered saline (PBS), in three different experimental set-ups. An isotype-matched control antibody (MOPC21 or MAb-170) and PBS injection served as controls. The ovarian cancer cell line NIH:OVCAR-NU-3 was injected IP at 1 x 10(6) cells/mouse or subcutaneously (SC) at 4 x 10(6) cells/mouse. Human-PBL-SCID/BG mice were either immunized before injection of tumor cells, along with tumor cells or after small tumors were established (2 weeks after transplantation). Antibody injections were repeated twice in 2-week intervals. Functional and cellular characterization of serum and PBL from these mice demonstrated the successful engraftment of a human immune system in those mice. All three experiments showed that OvaRex MAb-B43.13 treatment could (a) delay or prevent development of tumors; (b) reduce the size of small established tumors (SC tumor injection) or suppress ascites formation; (c) delay tumor growth when injected prior to tumor implantation; and (d) prolong the survival of the mice (i.p. tumor injection).

Animals↗

PubMed1993

Analysis of human blood cell development in the SCID-hu mouse, an in vivo replica of the human fetal hematopoietic system.

Human fetal blood tissues implanted in the SCID immuno-deficient mouse are tolerated and develop considerably. The bone marrow maintains its autonomous hematopoietic function for several months. Conversely, thymic lymphopoiesis can continue over the long term only in the presence of an appropriate source of stem cells. This in vivo replica of the human blood system can be used to test the hematogenic abilities of candidate populations of human hematopoietic stem cells, as suggested by the hematogenic reconstitution of human thymus and marrow in SCID mice obtained from purified CD34+ precursors. In the same model, hematogenic activity of CD34+ cells was limited to the sub-population of these precursors coexpressing the antigen Thy-1. These results, combined with those of in vitro analyses, suggest that the population of CD34+ Thy-1+ components of fetal liver and of the bone marrow is extremely rich in human hematopoietic stem cells.

Animals↗

PubMed1994

Rapid-high, syncytium-inducing isolates of human immunodeficiency virus type 1 induce cytopathicity in the human thymus of the SCID-hu mouse.

Clinical deterioration in human immunodeficiency virus type 1 (HIV-1) disease is associated with an increased viral burden in the peripheral blood and a loss of circulating CD4+ T cells. HIV-1 isolates obtained prior to this stage of disease often have a "slow-low," non-syncytium-inducing (NSI) phenotype, whereas those obtained afterwards are often characterized as "rapid-high" and syncytium inducing (SI). Paired NSI and SI isolates from two different patients were inoculated into the human thymus implants of SCID-hu mice. The two slow-low, NSI isolates replicated to minimal levels in the grafts and did not induce thymocyte depletion. In contrast, the two SI isolates from the same patients showed high levels of viral replication and induced a marked degree of thymocyte depletion, accompanied by evidence of programmed cell death. These observations reveal a correlation between the replicative and cytopathic patterns of HIV-1 isolates in vitro and in the SCID-hu mouse in vivo and provide direct evidence that the biological phenotype of HIV-1 switch may be a causal and not a derivative correlate of HIV-1 disease progression.

Acquired Immunodeficiency Syndrome↗

PubMed1996

HIV-1-associated pathology in hemato-lymphoid organs and the experimental evaluation in the SCID-hu mouse.

A variety of possible mechanisms for the loss of CD4+ T cells has been proposed, such as direct cytopathic effects by HIV-1 infection, and indirect induction of apoptosis. However, the fundamental picture of major and central pathogenic processes for the decay of immune systems is still missing in understanding the pathogenic mechanisms of HIV-1 infected humans. It is more appropriate to expand our focus onto entire organ systems involved in the development of immune system such as bone marrow and thymus. From the observations in the clinical studies, HIV-1 causes a variety of pathology on the T cell development pathway even from the hematopoietic progenitors and immature thymocytes, which should have a substantial impact on the failure of T cell homeostasis in the periphery. The SCID-hu mouse constructed by surgical implantation of human fetal hemato-lymphoid organs into the immunodeficient mouse has been used for the experimental evaluation of various parameters associated with HIV-1 infection and hematosuppression. Given the apparently normal structure and function of the human implants, the SCID-hu bone and Thy/Liv mice would appear to be potentially reliable models for the analysis of human physiology and patho-physiology.

AIDS-Related Opportunistic Infections↗

PubMed1995

Phosphorothioate oligonucleotides reduce melanoma growth in a SCID-hu mouse model by a nonantisense mechanism.

In our efforts to investigate the biologic role of Ha-ras oncogenes in human melanoma by Ha-ras phosphorothioate antisense oligonucleotides, we observed that antisense, sense, and scrambled control oligonucleotides at a concentration of 10 microM all similarly and strongly inhibited growth of our human melanoma target cell line SK-2 in vitro but without specific decrease of the target protein. Cell numbers with respect to the untreated control were reduced by 84% +/- 4.2% (ISD), 82.9% +/- 3.6%, and 84% +/- 3%, respectively. In vivo studies in a SCID-hu mouse model confirmed these findings. Both antisense and sense control oligonucleotides administered through osmotic pumps significantly (p < 0.006) reduced the mean tumor weight (1.5 g +/- 0.4 g and 1.8 g +/- 0.8 g, respectively) in comparison with saline-treated (5.7 g +/- 0.7 g) or untreated control animals (5.8 g +/- 1.0 g). The vascularity of oligonucleotide-treated tumors was greatly reduced. Clinical signs of oligonucleotide-related toxicity were not observed, and there was no evidence of histopathologic alterations in a variety of mouse tissues. We could demonstrate that the antimelanoma effects can be abrogated in vitro by adding basic fibroblast growth factor (bFGF). In the context of the importance of bFGF in melanocyte biology and angiogenesis, we argue in favor of an interaction between polyanionic phosphorothioate oligonucleotides and bFGF in our melanoma system. These findings stress the notion that phosphorothioate oligonucleotides may be promising antineoplastic lead compounds capable of employing antitumor effects by mechanisms other than specific inhibition of gene expression.

Animals↗

PubMed2002

TCR gamma delta+ and CD161+ thymocytes express HIV-1 in the SCID-hu mouse, potentially contributing to immune dysfunction in HIV infection.

The vast diversity of the T cell repertoire renders the adaptive immune response capable of recognizing a broad spectrum of potential antigenic peptides. However, certain T cell rearrangements are conserved for recognition of specific pathogens, as is the case for TCRgammadelta cells. In addition, an immunoregulatory class of T cells expressing the NK receptor protein 1A (CD161) responds to nonpeptide Ags presented on the MHC-like CD1d molecule. The effect of HIV-1 infection on these specialized T cells in the thymus was studied using the SCID-hu mouse model. We were able to identify CD161-expressing CD3(+) cells but not the CD1d-restricted invariant Valpha24/Vbeta11/CD161(+) NK T cells in the thymus. A subset of TCRgammadelta cells and CD161-expressing thymocytes express CD4, CXCR4, and CCR5 during development in the thymus and are susceptible to HIV-1 infection. TCRgammadelta thymocytes were productively infectable by both X4 and R5 virus, and thymic HIV-1 infection induced depletion of CD4(+) TCRgammadelta cells. Similarly, CD4(+)CD161(+) thymocytes were depleted by thymic HIV-1 infection, leading to enrichment of CD4(-)CD161(+) thymocytes. Furthermore, compared with the general CD4-negative thymocyte population, CD4(-)CD161(+) NK T thymocytes exhibited as much as a 27-fold lower frequency of virus-expressing cells. We conclude that HIV-1 infection and/or disruption of cells important in both innate and acquired immunity may contribute to the overall immune dysfunction seen in HIV-1 disease.

Animals↗

PubMed1997

Immunotherapy with low-dose interleukin-2: rationale for prevention of immune-deficiency-associated cancer.

PURPOSE: Congenital, acquired, and some iatrogenically induced immune deficiencies are characterized by an increased incidence of viral-associated cancers. Preclinical and clinical studies were conducted to understand the pathogenesis of immune-deficiency-associated cancer and its response to low-dose recombinant interleukin-2 (rIL-2) therapy, with the ultimate goal of applying this or other immune therapy in the treatment or prevention of immune-deficiency-associated lymphoma. METHODS: We have used the severe combined immune-deficient (SCID) mouse engrafted with human peripheral blood lymphocytes (PBL) from healthy Epstein-Barr virus seropositive donors to study the pathogenesis of malignant B-cell lymphoproliferative disease that commonly occurs in some immune-deficient patients. In this chimeric human (hu)-PBL-SCID mouse model, administration of daily low-dose rIL-2 interacts with murine natural killer cells and human CD8+ T cells to prevent the outgrowth of human Epstein-Barr virus lymphoproliferative disease. We have utilized the information gained from this chimeric mouse model to perform a phase I study of daily, subcutaneous, low-dose rIL-2 therapy in patients with both acquired immune deficiency syndrome (AIDS) and cancer. RESULTS: Plasma concentrations of rIL-2 were achieved in vivo comparable to those seen in our hu-PBL-SCID model, in the absence of significant (grade 3) clinical toxicity or an increase in the plasma human immune deficiency virus (HIV) RNA level. Significant expansion in human cells, particularly the CD3-CD56bright natural killer cell subset, resulted after 6 weeks of therapy. Results of the hu-PBL-SCID mouse model and the phase I study have led to a national trial of low-dose rIL-2 therapy in AIDS-associated lymphoma. CONCLUSION: Daily low-dose rIL-2 therapy may be effective in treating or preventing AIDS-associated lymphoma without amplifying HIV replication.

Acquired Immunodeficiency Syndrome↗