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PubMed2000

Latent herpes simplex virus-1 infection in SCID mice transferred with immune CD4+T cells: a new model for latency.

In C.B-17 severe combined immunodeficiency (SCID) mice, corneal challenge with herpes simplex virus-1 (HSV-1) KOS strain usually leads to fatal encephalitis. With the transfer of T cells from immunized BALB/c mice, these SCID mice developed a latent HSV-1 infection. In order to determine the responsible T cell subset, fractionated immune T cells were transferred. Those SCID mice transferred with immune CD4+T cell-enriched fraction developed latent HSV-1 infection in their trigeminal ganglia. Their splenocytes had an increased percentage of CD4+T cells and showed a proliferative response against HSV-1. The transfer of CD8+T cells increased survival in the acute infection, but their engraftment seemed less needed for latency than that of CD4+T cells. Mice that received immune serum survived without developing latent HSV-1 infection. Some latently infected SCID mice had anti-HSV antibodies while others did not, indicating that the engraftment of antibody-producing B cells was not required for latency. Thus, immune CD4+T cells were important for the survival of SCID mice with latent HSV-1 infection. This animal model should be useful for investigation of latency/reactivation of HSV-1.

Adoptive Transfer↗

PubMed1995

Leukemic cell growth in SCID mice as a predictor of relapse in high-risk B-lineage acute lymphoblastic leukemia.

Mice with severe combined immunodeficiency (SCID) provide a model system to examine the in vivo homing, engraftment, and growth patterns of normal and malignant human hematopoietic cells. The relation between leukemic cell growth in this model and the treatment outcome in patients from whom cells were derived has not been established. Leukemic cells from 42 children with newly diagnosed high-risk B-lineage acute lymphoblastic leukemia were inoculated intravenously into CB.17 SCID mice. Mice were killed at 12 weeks or when they became moribund as a result of disseminated leukemia. All mice were necropsied and subjected to a series of laboratory studies to assess their burden of human leukemic cells. Twenty-three patients whose leukemic cells caused histopathologically detectable leukemia in SCID mice had a significantly higher relapse rate than the 19 patients whose leukemic cells did not (estimated 5-year event-free survival: 29.5% v 94.7%; 95% confidence intervals, 11.2% to 50.7% v 68.1% to 99.2%; P < .0001 by log-rank test). The occurrence of overt leukemia in SCID mice was was a highly significant predictor of patient relapse. The estimated instantaneous risk of relapse for patients whose leukemic cells caused overt leukemia in SCID mice was 21.5-fold greater than that for the remaining patients. Thus, growth of human leukemic cells in SCID mice is a strong and independent predictor of relapse in patients with newly diagnosed high-risk B-lineage acute lymphoblastic leukemia.

Animals↗

PubMed2000

Unexpected rearrangement and expression of the immunoglobulin lambda1 locus in scid mice.

In severe combined immunodeficient (scid) mice, V(D)J recombination is severely impaired due to a recessive mutation (scid). Thus, we were surprised to find in this study that Vlambda1-Jlambda1 rearrangement is routinely detectable in scid fetal liver, adult bone marrow, and spleen in the apparent absence of completed VH-DJH and Vkappa-Jkappa rearrangements. Particularly surprising, we found the level of Vlambda1-Jlambda1 rearrangement in scid fetal liver to be comparable to that in fetal liver of wild-type mice. The majority of scid Vlambda1-Jlambda1 rearrangements contained abnormal deletions at the VJ junction, consistent with the known effect of scid. However, approximately 15% of Vlambda1-Jlambda1 rearrangements lacked abnormal deletions. Productive lambda1 transcripts resulting from in-frame rearrangements were readily detectable in scid adult bone marrow and spleen, consistent with our ability to detect lambda1-expressing cells by flow cytometry in the spleens of bcl-2-transgenic scid mice. Strikingly, lambda1 transcripts from individual scid mice often showed VJ junctional sequences with the same recurring palindromic (P) additions of three, four, or five nucleotides. To account for these findings, we suggest that (a) nonhomologous end joining of Vlambda1 and Jlambda1 coding ends in fetal B lineage cells may not be (severely) impaired by scid; (b) recurring P additions in scid lambda1 transcripts may reflect certain molecular constraints imposed by scid on the resolution of Vlambda1 and Jlambda1 hairpin coding ends; and (c), scid lymphocytes with productively rearranged Vlambda1 and Jlambda1 elements may differentiate into recombinase-inactive cells and emigrate from bone marrow to spleen.

Animals↗

PubMed1998

Study of Dengue virus infection in SCID mice engrafted with human K562 cells.

Here we report that severe combined immunodeficient (SCID) mice engrafted with human K562 cells (K562-SCID mice) can be used as an animal model to study dengue virus (DEN) infection. After intratumor injection into K562 cell masses of PL046, a Taiwanese DEN-2 human isolate, the K562-SCID mice showed neurological signs of paralysis and died at approximately 2 weeks postinfection. In addition to being detected in the tumor masses, high virus titers were detected in the peripheral blood and the brain tissues, indicating that DEN had replicated in the infected K562-SCID mice. In contrast, the SCID mice were resistant to DEN infection and the mock-infected K562-SCID mice survived for over 3 months. These data illustrate that DEN infection contributed directly to the deaths of the infected K562-SCID mice. Other serotypes of DEN were also used to infect the K562-SCID mice, and the mortality rates of the infected mice varied with different challenge strains, suggesting the existence of diverse degrees of virulence among DENs. To determine whether a neutralizing antibody against DEN in vitro was also protective in vivo, the K562-SCID mice were challenged with DEN-2 and received antibody administration at the same time or 1 day earlier. Our results revealed that the antibody-treated mice exhibited a reduction in mortality and a delay of paralysis onset after DEN infection. In contrast to K562-SCID, the persistently DEN-infected K562 cells generated in vitro invariably failed to be implanted in the mice. It seems that in the early stage of implantation, a gamma interferon activated, nitric oxide-mediated anti-DEN effect might play a role in the innate immunity against DEN-infected cells. The system described herein offers an opportunity to explore DEN replication in vivo and to test various antiviral protocols in infected hosts.

Animals↗

PubMedDate not supplied

Experimental systemic cryptococcosis in SCID mice.

The susceptibility of severe combined immune deficiency (SCID) mice to experimental systemic cryptococcosis was studied. SCID mice were at least 16-fold more susceptible to lethal infection than were immunocompetent control mice (P < 0.001). Histological assessment showed that control mice responded with a granulomatous inflammatory response, whereas SCID mice showed no evidence of a cellular host response. In a therapeutic study, 5 mg kg-1 day-1 of fluconazole caused a significant reduction in the infectious burden in the spleen, liver, kidney and lungs of treated mice compared with no treatment. These results indicate that a model of systemic cryptococcosis with meningitis in SCID mice may have utility in the study of immunology and therapy of this disease in the severely immunocompromised host.

Animals↗

PubMed2003

[Model of B immunoblastic lymphomas in the Hu-PBL-SCID mice].

OBJECTIVE: To constitute a model of B immunoblastic lymphomas in the Hu-PBL-SCID mice. METHODS: The SCID mice were reconstituted by intraperitoneal injection (i.p.) of 5 x 10(7) human lymphocytes from Epstein-Barr virus (EBV) seronegative individuals. After one week, the SCID mice were inoculated with EBV by i.p. injection, and subjected to the investigation of whether there was any tumor in the abdomen of such SCID mice four weeks later. The characteristics of the found tumor was observed by the methods of Hematoxylin-eosin (HE) stain, immunohistochemical staining and polymerase chain reaction (PCR). RESULTS: Compared with the control groups, all the EBV-infected Hu-PBL-SCID mice had abdominal solid tumors [(32 +/- 12.5) mm3] developed, often located in the liver. HE staining and immunohistochemical staining showed the tumors were human B cell lymphomas. EBV DNA could be detected in the tumors by the PCR. CONCLUSIONS: The model of B immunoblastic lymphomas in the Hu-PBL-SCID mice is successfully constituted, and may well be useful to the human tumor immunological study.

Animals↗

PubMed1994

Transfer of Sjögren's syndrome-like autoimmune lesions into SCID mice and prevention of lesions by anti-CD4 and anti-T cell receptor antibody treatment.

We describe the successful transfer of murine Sjögren's syndrome-like autoimmune lesions from MRL/lpr mice (H-2k) to severe combined immunodeficiency (SCID) mice (H-2d) and prevention of lesions by anti-CD4 and -T cell receptor V beta 8 antibody treatment. Mononuclear cells (1 x 10(6)) isolated from the inflamed submandibular salivary gland tissues of MRL/lpr mice were transferred intraperitoneally into SCID mice. Autoimmune lesions resembling those seen in Sjögren's syndrome developed in the salivary and lacrimal glands of SCID mice 8 weeks after the injection, whereas other organs did not show any lesion. This pathology resembles Sjögren's syndrome in humans involving both the salivary and lacrimal glands. Immunohistochemically, a major proportion of these infiltrating cells in transferred SCID mice were CD4+ and V beta 8+. When the spleen cells from MRL/lpr mice were injected, severe inflammatory lesions, probably resulting from a graft-versus host reaction, were observed in multiple organs of SCID mice. The disease could not be induced by intraperitoneal administration of the sera from MRL/lpr mice, or of the spleen cells from C3H/He (H-2k) and BALB/c (H-2d) mice. We detected autoantibody production specific for the salivary gland tissue in sera from transferred SCID mice. Moreover, we found that the lesions were prevented by administration of the isolated cells treated in vitro with anti-CD4 and anti-V beta 8 monoclonal antibodies. These results suggest that CD4- and V beta 8-bearing T cells are involved in recognizing an autopeptide and triggering autoimmunity in the salivary and lacrimal glands, and therapies designed with anti-CD4 and anti-V beta 8 antibodies may prove effective in treating the murine autoimmune disease.

Animals↗

PubMed1994

Macrophage activation and innate resistance to infection in SCID mice.

Resistance to infection against a variety of pathogens requires the co-ordinated interaction of both the innate and acquired immune responses. Mice bearing the SCID mutation are devoid of T and B cells but retain elements of the innate immune system including natural killer (NK) cells, macrophages, granulocytes and complement proteins. Using the SCID model we have identified a T cell independent mechanism of macrophage activation mediated by the secretion of IFN-gamma from NK cells. This process occurs in response to a variety of parasites and bacteria including Listeria monocytogenes, and is strictly regulated both in vitro and in vivo by cytokines such as IL-2 and IL-10. Here we discuss the mechanisms of NK cell activation and regulation and describe a new model of opportunistic infection in SCID mice with the AIDS related pathogen Cryptosporidium parvum.

Animals↗

PubMed1992

Allogeneic chimerism in scid mice after neonatal transfer of bone marrow.

Allogeneic chimeras are valuable tools for studies of complex immune cell interactions in vivo. Mice with severe combined immune deficiency (scid) should be ideal hosts for chimerism with allogeneic bone marrow cells as these animals lack mature T and B lymphocytes capable of reacting against donor alloantigens. However, it has been difficult to achieve full reconstitution of adult scid mice even using coisogenic bone marrow grafts without prior irradiation of the recipient. We explored ways to generate complete reconstitution of scid mice with allogeneic bone marrow. Unirradiated adult scid recipients of allogeneic bone marrow were only marginally reconstituted. Adult scid mice pretreated with 250 R were reconstituted with allogeneic bone marrow as measured by serum IgM concentration, peripheral lymphoid cellularity, and mitogen responses, but a potentially important immunologic deficit was found in these mice: 250 R caused a 70% loss of scid macrophages and dendritic cells which persisted at least 5 months. By contrast, when scid mice were injected i.p. with allogeneic bone marrow within the first 24 h after birth, rapid and complete reconstitution of both T and B cell lineages was achieved, and the animals had APC that were both donor and host in origin. Considering the extent and duration of engraftment (43 wk) by allogeneic cells in neonatally transplanted scid mice, it was anticipated that their bone marrow would be chimeric. However, the bone marrow contained very few donor-derived cells, suggesting that lymphopoiesis may be taking place in other organs in these chimeras.

Animals↗

PubMed1991

Immunization with baculovirus-expressed recombinant rotavirus proteins VP1, VP4, VP6, and VP7 induces CD8+ T lymphocytes that mediate clearance of chronic rotavirus infection in SCID mice.

Clearance of chronic murine rotavirus infection in SCID mice can be demonstrated by adoptive transfer of immune CD8+ T lymphocytes from histocompatible donor mice immunized with a murine homotypic rotavirus (T. Dharakul, L. Rott, and H.B. Greenberg, J. Virol 64:4375-4382, 1990). The present study focuses on the protein specificity and heterotypic nature of cell-mediated clearance of chronic murine rotavirus infection in SCID mice. Heterotypic cell-mediated clearance was demonstrated in SCID mice infected with EDIM (murine) rotavirus after adoptive transfer of CD8+ T lymphocytes from BALB/c mice that were immunized with a variety of heterologous (nonmurine) rotaviruses including Wa (human, serotype 1), SA11 and RRV (simian, serotype 3), and NCDV and RF (bovine, serotype 6). This finding indicates the serotypic independence of T-cell-mediated rotavirus clearance. To further identify the rotavirus proteins that are capable of generating CD8+ T cells that mediate virus clearance, donor mice were immunized with SF-9 cells infected with a baculovirus recombinant expressing one of the following rotavirus proteins: VP1, VP2, NS53 (from RF), VP4, VP7, NS35 (from RRV), VP6, and NS28 (from SA11). SCID mice stopped shedding rotavirus after receiving CD8+ T cells from mice immunized with VP1, VP4, VP6, and VP7 but not with VP2, NS53, NS35, NS28, or wild-type baculovirus. These results suggest that heterotypic cell-mediated clearance of rotavirus in SCID mice is mediated by three of the major rotavirus structural proteins and by a putative polymerase protein.

Animals↗

PubMed1993

Specific antibody production to a recall or a neoantigen by SCID mice reconstituted with human peripheral blood lymphocytes.

To explore the extent of immune reconstitution of SCID mice by human peripheral blood lymphocytes (hu-PBL-SCID mice), we studied the production of immunoglobulin isotypes and specific antibody (Ab) by the engrafted human cells. Human IgG was detectable in 94% of hu-PBL-SCID mice. IgE synthesis by hu-PBL-SCID mice correlated with the IgE levels observed in human donors. All SCID mice receiving PBL obtained from human donors previously immunized with the T-cell-dependent Ag, bacteriophage phi x 174 (phage), produced phage neutralizing antibody. Quantity and quality (Ig isotypes) of phage-specific Ab produced by hu-PBL-SCID mice correlated with that observed in the donor serum. Human B cells alone failed to engraft, and T cells were required for the production of Ig and anti-phage Ab. Phage-specific Ab production occurred without direct Ag exposure of the hu-PBL-SCID mice, suggesting that the specific Ab production was induced directly by polyclonal activation of the engrafted human cells. Intravenous phage injections given 4 wk after cell transfer failed to further increase the anti-phage Ab titer. Phage neutralizing Ab production could not be boosted if spleen cells obtained from hu-PBL-SCID mice were cultured in the presence of Ag. However, hu-PBL-SCID mice produced increased amounts of anti-phage Ab, providing they were injected with phage at the time of cell transfer. Injection of phage at the time of cell transfer, but not 4 wk later, to mice receiving PBL from nonimmunized donors induced production of minute amounts of anti-phage Ab. We conclude that human peripheral blood lymphocytes transferred into SCID mice become maximally stimulated presumably by xenogeneic murine Ag, resulting in polyclonal expansion of the graft and spontaneous production of Ab to Ag the human donor was previously exposed to, and in loss of responses to subsequent Ag exposure. Ab production to neoantigen, however, can be induced and that to recall Ag can be modified if PBL are exposed to Ag at the time of cell transfer.

Adult↗

PubMed1992

Mediation of skin allograft rejection in scid mice by CD4+ and CD8+ T cells.

We analyzed the role of CD4+ and CD8+ T cells in H-2-disparate skin allograft rejection in the mutant mouse strain C.B-17/Icr scid with severe combined immunodeficiency. On the day of skin allografting, scid mice were adoptively transferred with negatively selected CD4+ or CD8+ splenocytes from normal unsensitized C.B-17/Icr mice. These populations were obtained using a double-mAb--plus--complement elimination protocol using anti-CD4 or anti-CD8 mAb that resulted in no detectable CD4+ or CD8+ cells by FACS and negligible numbers of cytolytic T lymphocytes by limiting dilution analysis in anti-CD8 treated populations. Spleen cells were removed from grafted mice at the time of rejection and were tested in vitro for antidonor reactivity in several assays: mixed lymphocyte culture, cell-mediated lympholysis, and LDA for CTL and for IL-2-producing HTL. The presence of Thy 1.2+, CD4+, or CD8+ cells was determined by FACS. All control C.B-17 mice and scid mice adoptively transferred with nondepleted CD4+, and CD8+ cells rejected skin allografts with similar mean survival times (15.6 +/- 1.5, 18.8 +/- 3.4, 18.0 +/- 5.4, respectively), whereas control scid mice retain skin allografts indefinitely (all greater than 100 days). C.B-17 syngeneic grafts survived indefinitely in all groups. At the time of rejection, splenocytes from scid mice receiving CD4+ cells had negligible donor-specific cytotoxicity in CML and negligible numbers of CTL by LDA, but demonstrated a good proliferative response in MLC and IL-2-producing cells by LDA (frequency = 1/1764). There were no detectable CD8+ cells present by FACS analysis. Conversely, splenocytes from scid mice adoptively transferred with CD8+ cells had strong donor-specific cytotoxicity in CML (58.8% +/- 16.1%) and CTL by LDA (frequency = 1/3448), but no significant proliferation was detected in MLC. There were no detectable CD4+ cells by FACS, but there were small numbers of IL-2-producing cells by LDA (frequency = 1/10,204). These data demonstrate that CD4+ cells adoptively transferred into scid mice are capable of mediating skin allograft rejection in the absence of any detectable CD8+ cells or significant functional cytolytic activity. The adoptive transfer of CD8+ cells also results in skin allograft rejection in the absence of detectable CD4+ cells. The detection of small numbers of IL-2 secreting cells in these mice may indicate that CD(8+)-mediated allograft rejection in this model is dependent on IL-2-secreting CD8+ cells.

Animals↗

PubMed1991

Successful engraftment of human postnatal thymus in severe combined immune deficient (SCID) mice: differential engraftment of thymic components with irradiation versus anti-asialo GM-1 immunosuppressive regimens.

To develop a model of human thymus growth in vivo, we have implanted postnatal human thymus under the renal capsule of severe combined immune deficient (SCID) mice and assayed for graft survival and graft characteristics 1-3 mo after engraftment. Three groups of SCID mice were engrafted with postnatal human thymus: untreated SCID mice, SCID mice pretreated with 400 cGy of gamma irradiation 1-5 d before engraftment, and SCID mice treated with intraperitoneal anti-asialo GM-1 antiserum every 4-5 d during engraftment. In the untreated group of SCID mice, only 37% of grafts survived and consisted of human thymic microenvironment components and human immature thymocytes. Irradiation of SCID mice before engraftment improved survival of human thymic grafts to 83%, but these grafts were largely devoid of thymocytes and contained only thymic microenvironment components with large numbers of thymic macrophages. Treatment of SCID mice with anti-asialo GM-1 antiserum throughout the engraftment period also promoted human thymus engraftment (70%) and induced SCID B cell Ig production (SCID[Ig+]) in 38% of animals. In SCID(Ig-) anti-asialo GM-1-treated mice, the human thymic grafts were similar in content to those in untreated SCID mice. However, in anti-asialo GM-1-treated animals with grafts that became SCID(Ig+), all animals were found to have mouse-human chimeric grafts in that the human thymic microenvironment (human fibroblasts, thymic epithelium, vessels) was colonized by murine T cells. These data demonstrate that human postnatal thymus will grow as xenografts in SCID mice, and that the components of human thymus that engraft are dependent on the immunosuppressive regimen used in recipient mice. A striking finding in this study was the induction of T and B lymphopoiesis in SCID mice by abrogation of NK cell activity with in vivo anti-asialo GM-1 treatment. These data strongly suggest that asialo GM-1+ NK cells and/or macrophages play a role in mediation of suppression of lymphopoiesis in SCID mice.

Animals↗

PubMed1992

In vitro preactivated human T cells engraft in SCID mice and migrate to murine lymphoid tissues.

Mice with severe combined immunodeficiency (SCID) accept grafts of human T and B lymphocytes derived from resting peripheral blood mononuclear cells (PBMC). We wished to determine whether activated human T cells engraft and migrate into lymphoid tissues in SCID mice. PBMC (50 x 10(6)) activated in vitro in a 4-day mixed lymphocyte culture (MLC) were injected into the peritoneum of 12 SCID mice. In 11 of 12 animals killed at 3 or 4 weeks after injection, human cells were detected in cells pooled from lymphoid organs by flow cytometry and by immunohistochemical staining of frozen tissue sections. The percentage of CD45+ cells in the 11 mice ranged from 2% to 45% and the absolute numbers of CD45+ cells recovered from lymphoid organs ranged from 4 x 10(6) to 90 x 10(6). Up to 93% of the human cells expressed the CD3 antigen together with either CD4 or CD8. Human T cells were localized in periarteriolar areas in murine spleens, whereas in the lymph nodes and gut mucosa, the T cells did not show the pattern for T-dependent areas found in human lymphoid tissue. Numerous human plasma cells were detected in the spleen and gut mucosal crypts of engrafted SCID mice. Human IgG was detected in the serum of all 11 engrafted SCID mice. The functional activity of human T cells recovered from murine splenic tissue was very low 3-4 weeks after engraftment.

Animals↗

PubMed2000

Anti-tetanus toxoid antibody production and protection against lethal doses of tetanus toxin in hu-PBL-SCID mice.

BACKGROUND: In this study, severe combined immunodeficiency (SCID) mice, which permit the survival of lymphoid cells of human origin, were used to study the human anti-tetanus immune response. METHODS: Human peripheral blood lymphocytes (hu-PBL) obtained from 88 healthy donors (aged from 18 to 62) were transplanted into SCID mice, and anti-tetanus toxoid (Ttd) antibody production and protection against lethal doses of tetanus toxin (Ttx) were investigated in the hu-PBL-SCID mice. RESULTS: The transfer of human PBL evoked significant human anti-Ttd IgG antibody production for 37.5% of the donors. After in vivo immunization, the percentage of donors with PBL exhibiting positive anti-TtD IgG production in the mice increased to 54.5%. Mean anti-Ttd IgG levels in the sera were also significantly elevated in response to immunization. The mean IgG titer for the mice injected with PBL from donors under the age of 40 was significantly higher than that of the mice injected with PBL from donors aged 40 or older. Four weeks after the cell transfer, the mice were challenged with Ttx. The induction of protection against Ttx challenge was observed mostly in mice with PBL transferred from donors under the age of 40. In vivo immunization in SCID mice with Ttd increased the number of cases of resistance to Ttx. CONCLUSIONS: These results suggest that hu-PBL-SCID mice might serve as a tool for predicting the protective ability against pathogens in PBL donors and also for evaluating vaccine efficacy.

Adolescent↗

PubMed2005

Prolonged skin allograft survival in Scid mice reconstituted with isogeneic bone marrow stem cell antigen-1-positive cells and thymus tissue.

INTRODUCTION: Many studies indicate that tolerance induction is much more dependent on the maturation status of lymphocytes than the age of the animal. We hypothesized that direct persistent contact of bone marrow stem cells with graft alloantigen will result in tolerance to that antigen in the adult animal. MATERIAL AND METHODS: Severe combined immunodeficient mice (CB-17-Scid, H-2b) were reconstituted with isogeneic bone marrow stem cell antigen-1 (Sca-1)-positive cells and grafted with fetal thymus (BMSC-T), followed by transplant of allogeneic skin grafts from C57BL/6 (H-2d) mice. The control group include CB-17 non-Scid mice, CB-17-Scid mice, and CB-17 Scid mice pretransplanted with nonmodified isogeneic bone marrow cells and fetal thymus (BMC-T). RESULTS AND DISCUSSION: Skin allograft survival was significantly prolonged in the group pretransplanted with isogeneic BMSC-T compared the group of non-Scid mice and the group of Scid mice pretransplanted with BMC-T (59.6 days vs 7.1 days vs 11.7 days). In 2 of 10 mice pretransplanted with BMSC-T, the skin allografts transplanted immediately after BMSC-T survived for more than 100 days, but the third-party skin allografts transplanted at 100 days after BMSC-T transplant were rejected. The results suggest direct persistent contact of bone marrow Sca-1-positive cells with graft alloantigen may be a feasible approach to prolong allograft survival and induce tolerance in a small fraction of adult animals.

Animals↗

PubMed1994

Human peripheral blood lymphocyte reconstituted severe combined immunodeficient (hu-PBL-SCID) mice. A model for human islet allograft rejection.

Severe combined immunodeficient (SCID) mice have become a promising tool for the development of models of human immunologic process. We report the development of a reproducible technique for engrafting SCID mice with human PBL (hu-PBL-SCID). Our results show that a booster injection of anti-CD3 antibody stimulated human lymphocytes given 2 days after the initial injection of lymphocytes will improve the efficiency of chimera establishment to 86.7% (13 out of 15). There was also good correlation among detection of human Ig, human CD3+ cells, and human DNA by polymerase chain reaction amplification in the circulation of hu-PBL-SCID mice. Questions remain concerning the immune function of the human lymphoid cells in the SCID mouse. In this study, we analyzed the ability of human T cells in SCID mice to reject human islet allografts transplanted under the kidney capsule. Human islet allograft function assessed by human C-peptide levels demonstrated failure of islet allografts within 21 days after transplantation in hu-PBL-SCID. In contrast, human islets grafted in unreconstituted SCID mice continued to function for greater than 60 days. Recovered human T cells from rejected islets of hu-PBL-SCID mice displayed specific cytolytic activity against HLA class I-matched islets, while the recovered cells from spleen of hu-PBL-SCID mice showed minimal specific cytotoxicity against islets. These results suggest that graft-infiltrating lymphocytes were activated by the engrafted islets within the hu-PBL-SCID, causing the eventual rejection of the human islet allograft. Thus, engraftment of the anti-CD3 antibody-primed human PBL results in a mouse-human chimera with a functionally competent human immune system that is capable of rejecting a human islet allograft.

Animals↗

PubMed1998

Engraftment of ex vivo expanded and cycling human cord blood hematopoietic progenitor cells in SCID mice.

The ability of human hematopoietic cells to engraft SCID mice provides a useful model in which to study the efficiency of retroviral gene transfer and expression in primitive stem cells. In this regard, it is necessary to determine whether SCID mice can be engrafted by cycling human hematopoietic progenitor cells. Human cord blood cells from 12 different donors were cultured in vitro for 6 days with interleukin-3 and stem cell factor. Phenotypic analysis indicated that hematopoietic cells were induced to cycle and the number of progenitors was expanded, thus making them targets for retroviral gene transfer. The cells were then transferred to SCID mice. Human hematopoietic progenitor cell engraftment was assessed up to 7 weeks later by growth of human progenitor cells in soft agar. After in vitro culture under conditions used for retroviral gene transfer, human cord blood hematopoietic cells engrafted the bone marrow and spleen of SCID mice. Interestingly, cultured cord blood cells engrafted after intraperitoneal but not after intravenous injection. Furthermore, engraftment of cord blood cells was observed in mice receiving no irradiation before transfer of the human cells, suggesting that competition for space in the marrow is not a limiting factor when these cells have been cultured. Administration of human cytokines after transfer of human cord blood cells to SCID mice was also not required for engraftment. Thus, engraftment of SCID mice with human hematopoietic cells cultured under conditions suitable for gene transfer may provide an in vivo assay for gene transfer to early human hematopoietic progenitor cells.

Animals↗