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PubMed1978

[Status of T- and B-lymphocytes in long living CBA--F1 (CBA X C57BL/6) chimeras].

Semiallogeneic chimeras were produced by injecting 3 X 10(7) spleen cells of mice CBA (H--2k, Mlsd) to lethally irradiated mice (CBA X C57BL/6)F1. Two days later recipients were given cyclophosphamide (CP), 2 mg per mouse, to prevent death of graft versus host reaction (GVHR). For 1.5--2 months after the creation of chimerism in 23 of 26 mice under study all cells producing antibodies to SRBC were represented by donor cells of H-2 phenotype; 3 mice were partial chimeras. Spontaneous blast transformation in the cultures of chimera spleen did not exceed the control level, and in the mixed lymphocyte culture chimera cells failed to proliferate on addition of irradiated lymphocytes (CBA X C57BL/6) F1. At the same time chimera gave intensive blast transformation to the irradiated lymphocytes of the third line of mice DBA/2 (H--2d, Mlsa). Among the chimera spleen cells no killers capable of destroying target cells of donor or recipient origin were revealed. Similar results were obtained in vivo: chimera cells gave no positive local GVHR after administration to mice (CBA X C57BL/6) F1. Prolonged chimerism was accompanied by a reactivity of donor T-lymphocytes to the recipient transplantation antigens. A blocking factor was revealed in the blood serum of chimeras. The substitution of donor lymphocytes for the recipient cells begins after 3 to 5 months. At the same period donor T-cell population reconstitutes partially the responsiveness to the recipient antigens and the blocking factor disappears from chimeras blood.

Animals↗
PubMed1986

Suppressor cells detected in murine bone marrow chimeras.

Bone marrow cells from BALB/c mice were transplanted into lethally X-irradiated C3H/He mice, either intravenously (i.v.) or intrasplenically (i.s.). Chimeras created by intrasplenic transplantation (designated i.s. chimeras) showed a higher survival rate than chimeras created by intravenous transplantation (designated i.v. chimeras). During the course of the study on the mechanisms which caused such a difference, suppressor cells were detected in the spleen of i.s. chimeras by means of MLR co-culture assay and CTL assay. Although these cells were also detected in i.v. chimeras, time course study of the suppressor activity against donor anti-host MLR in i.v. and i.s. chimeras showed some difference. Namely, the suppressor activity in the i.s. chimeras was more constant than that in the i.v. chimeras. This difference may induce a beneficial effect of i.s. bone marrow transplantation.

Animals↗
PubMed1997

Protection against autoimmune diabetes in mixed bone marrow chimeras: mechanisms involved.

After bone marrow transplantation, complete nonobese diabetic (NOD) into (NOD x C57Bl/10)F1 chimeras developed insulitis in 100% (7/7) and diabetes in 58% (7/12) of cases. In contrast, when mixed chimerism was induced, a near complete protection against insulitis (3/23, p < 0.0001 vs complete chimeras) and diabetes (0/25, p < 0.001 vs complete chimeras) was achieved even in chimeras with as few as 5% F1 cells. In cotransfer experiments, splenocytes from mixed chimeras failed to prevent diabetes, thus overruling a role for suppressor cells in protection. Whereas splenocytes from complete chimeras transferred diabetes into young irradiated NOD mice in all cases, NOD splenocytes from mixed chimeras only rarely transferred diabetes (3/16, p < 0.01 vs complete chimeras), suggesting that the latter cells had developed tolerance toward beta cells. To achieve this tolerance, the presence of an F1 thymus was not needed. Indeed, whereas splenocytes isolated from complete chimeras were diabetogenic when transferred into neonatally thymectomized irradiated NOD recipients (3/4), they failed to induce diabetes when transferred into neonatally thymectomized irradiated F1 recipients in case again a state of mixed chimerism was induced (0/4, p < 0.001 vs NOD recipients). Finally, a role for non-MHC Ags was demonstrated by experiments in F1 mice crossed between NOD and C57Bl/6, a strain congenic to C57Bl/10. Here protection against disease was only seen in the presence of high levels of F1 cells (>25%). In conclusion, mixed bone marrow chimerism can induce self-tolerance in autoimmunity prone NOD immune cells. This can be achieved extrathymically but may depend on non-MHC Ags and the level of chimerism.

Adoptive Transfer↗
PubMed1998

Functional characterization and visualization of a GABAA receptor-GFP chimera expressed in Xenopus oocytes.

The GABAA receptor is a ligand-gated chloride channel belonging to the superfamily of ligand-gated ion channels of which the nicotinic acetylcholine (nACh) receptor is prototypic. In the central nervous system the GABAA receptor mediates fast neuronal inhibition. To facilitate the study of this receptor, a GABAA receptor-green fluorescent protein (GABAAR-GFP) chimera was constructed by fusing green fluorescent protein (GFP) to the C-terminus region of the GABAA receptor alpha1 subunit. When expressed in Xenopus oocytes, this chimera responded in a manner indistinguishable from the wild-type GABAA receptor with respect to agonist potency, receptor desensitization, allosteric modulation, rectification, and ion selectivity of the channel. The addition of GFP to the GABAA receptor alpha1 subunit did not appear to alter the assembly or efficiency of expression of the GABAA receptor complex. The GABAAR-GFP chimera generated a strong fluorescent signal that was restricted to the animal pole of the oocyte plasma membrane. This signal was readily detectable using either epifluorescence or laser confocal microscopy. To confirm the extracellular location of the GFP portion of the chimera, non-permeabilized oocytes were immunolabeled with an anti-GFP antibody. Fluorescence microscopy showed that GFP was located extracellularly since it was accessible to the GFP antibody. These results confirm the predicted extracellular location of the C-terminus of the GABAA receptor alpha1 subunit and also demonstrate that GFP retains its fluorescent property when expressed extracellularly. The usefulness of the GABAAR-GFP chimera in receptor trafficking was investigated using non-hydrolyzable GTP analogues since GTP binding proteins participate in protein transport in oocytes. Microinjections of GTP-gamma-S but not GDP-beta-S reduced both GABA-gated chloride currents and cell surface GFP fluorescence in oocytes expressing the GABAAR-GFP chimera indicating that the chimera undergoes internalization upon stimulation of oocyte GTP-binding proteins. The results of the present study show that the GABAAR-GFP chimera is functionally similar to the wild-type GABAA receptor and can be used to study receptor trafficking in living cells. This is the first demonstration of a ligand-gated ion channel-GFP chimera for an ion channel belonging to this superfamily and also is the first example of the fusion of GFP to an extracellular domain of an integral membrane protein.

Anesthetics↗
PubMed1993

Calmodulin-cardiac troponin C chimeras. Effects of domain exchange on calcium binding and enzyme activation.

Calmodulin (CaM) and the cardiac isoform of troponin C (cTnC) are close structural homologs, but cTnC cannot activate most CaM target enzymes. To investigate structure-function relationships, we constructed a series of CaM.cTnC chimeras and determined their ability to bind Ca2+ and activate CaM target enzymes. Previously, we exchanged domain 1 and found that the chimeras exhibited profoundly impaired activation of smooth muscle myosin light chain kinase (smMLCK) and had differential effects on other CaM target enzymes (George, S. E., VanBerkum, M. F. A., Ono, T., Cook, R., Hanley, R. M., Putkey, J. A., and Means, A. R. (1990) J. Biol. Chem. 265, 9228-9235). One of the domain 1 chimeras was a potent competitive inhibitor of smMLCK. We now extend our study of CaM.cTnC chimeras by exchanging all of the remaining functional domains of CaM and cTnC. We determined the ability of the chimeras to bind Ca2+ and activate phosphodiesterase (PDE) and smMLCK. Chimeras containing both domains 3 and 4 of cTnC exhibited high affinity Ca2+ binding that was indistinguishable from cTnC, whereas chimeras containing either domain 3 or 4 of cTnC demonstrated Ca2+ affinity that was intermediate between CaM and cTnC. All of the CaM.cTnC chimeras showed near-maximal PDE activation but required 5-775-fold higher concentrations than CaM to produce half-maximal PDE activation. In contrast, all of the chimeras showed impaired ability to activate smMLCK, and some were potent competitive inhibitors of smMLCK activation by CaM.

Amino Acid Sequence↗
PubMed1989

Deletion of Mls-reactive T cells in H-2-compatible but Mls-incompatible bone marrow chimeras.

The cellular basis of tolerance induction to Mls-encoded antigens in radiation bone marrow (BM) chimeras has been investigated in two H-2-compatible strain combinations of AKR/J (H-2k, Thy-1.1, Mls-Ia) and C3H/He (H-2k, Thy-1.2, Mls-IIa). Sequential appearance of host- and donor-derived T cell subsets and T cell receptor gene messages occurred in the peripheral lymphoid organs of both irradiated AKR/J mice reconstituted with C3H/He BM cells (C3H/He-AKR/J chimera) and irradiated C3H/He mice reconstituted with AKR/J BM cells (AKR/J-C3H/He chimera). A large number of cells expressing T cell receptor gamma genes were detected in spleen on day 21 after reconstitution, while the normal level of alloreactivity was first detected in the spleen on day 56 after reconstitution in correlation with the appearance of appreciable levels of Thy-1 high cells and T cell receptor alpha and beta gene transcripts. T cells bearing V beta 6, that is strongly correlated with reactivity to antigens encoded by the Mls-Ia genetic locus, were virtually abolished in spleen on day 56 in both C3H/He-AKR/J chimera and AKR/J-C3H/He chimera. Furthermore, expression of V beta 3 gene transcripts, that are important for recognizing Mls-IIa, was undetected either in the peripheral lymphoid cells of AKR/J-C3H/He chimera or in those of C3H/He-AKR/J chimera. These results suggested that clonal elimination of self-reactive T cells bearing V beta 3 or V beta 6 was induced by both host-derived radioresistant cells and donor-derived repopulating cells in the thymus of radiation BM chimeras.

Animals↗
PubMed1990

Failure to find alloimmune memory in the resorption phenomenon of Botryllus cytomictical chimera.

It has been previously shown that mixed-cell chimeras may be established between different colonies of the compound tunicate Botryllus schlosseri given that they share one allele in common on the fusibility locus. However, one of the partners in each chimera is often resorbed. Here we tested for the existence of a memory component to this response, as measured by the accelerated interval to resorption of a second set of semiallogeneic colonies. Eight genetically unrelated colonies gave rise to eighteen chimeras. After a complete resorption of the "inferior" partners in these chimeras, secondary and tertiary sets of chimeras were established with some of them by fusion of the "superior" with naive subclones of the "inferior" partners. It is shown here that (a) when multiple chimeras are prepared using the same pair of colonies, subclones of only one of the partners are resorbed; (b) high variation in the time for resorption is recorded when several chimeras are prepared from any specific pair of colonies, and (c) the time for resorption is not related to the number of vessels connecting between the partners in the chimera, nor to their relative body sizes. Allospecific memory is not documented here and reasons for its absence are discussed.

Animals↗
PubMed1993

gld and lpr hematopoietic cell transfers: common and different serological features of the C57BL/6 chimeras.

Homozygosity for either the lpr (lymphoproliferation) or the gld (generalized lymphoproliferative disease) mutation in mice causes the development of strikingly similar hyperglobulinemia and lymphoproliferative syndromes. Nevertheless, previous studies of various C57BL/6 chimeras obtained by reconstitution of irradiated recipients with hematopoietic cells (HC), differing at the bg, gld, lpr, and/or nu loci, showed that the lpr and gld syndromes had distinct etiologies. The [lpr-->lpr], [gld-->gld], and [gld-->wild] chimeras developed lymphoid hyperplasia, while the [lpr-->wild, bg, or gld] and [nulpr-->wild or bg] chimeras developed a severe persistent lymphoid aplasia. We now show that the serological status (immunoglobulin (Ig) levels and Ig isotype distribution) of the [lpr-->lpr], [gld-->gld], and [gld-->wild] chimeras were roughly equivalent to those of genetic lpr and gld mice. Despite their lymphoid aplasia, all the [lpr-->non-lpr] chimeras displayed surprisingly normal serum Ig levels, similar to [wild-->wild] control chimeras, although always with some abnormal isotype profile. In fact, an early but transient increase of serum IgG1 levels was found in all [lpr-->wild, bg, or gld], [lpr-->lpr], [nulpr-->wild or bg], [wild-->lpr], and [gld-->wild or gld] types of chimeras. Despite a common early behavior, the host type and/or the gld or lpr HC origin may cause later divergences of the gld or lpr HC grafted chimeras.

Animals↗
PubMed2004

Attempts to enhance production of porcine chimeras from embryonic germ cells and preimplantation embryos.

Porcine embryonic germ (EG) cells share common features with porcine embryonic stem (ES) cells, including morphology, alkaline phosphatase activity and capacity for in vitro differentiation. Porcine EG cells are also capable of in vivo development by producing chimeras after blastocyst injection; however, the proportion of injected embryos that yield a chimera and the proportion of cells contributed by the cultured cells in each chimera are too low for practical use in genetic manipulation. Moreover, somatic, but not germ-line chimerism, has been reported from blastocyst injection using porcine ES or EG cells. To test whether efficiency of chimera production from blastocyst injection can be improved upon by changing the host embryo, we used as host embryos four groups according to developmental stage or length in culture: fresh 4-cell and 8-cell stage embryos subsequently cultured into blastocysts, fresh morulae, fresh blastocysts, and cultured blastocysts. Injection and embryo transfer of fresh and cultured blastocysts produced similar percentages of live piglets (17% versus 19%). Four piglets were judged to have a small degree of pigmentation chimerism, but microsatellite analysis failed to confirm chimerism in these or other piglets. Polymerase chain reaction analysis for detection of the porcine SRY gene in female piglets born from embryos injected with male EG cells identified six chimeras, at least one, but not more than two, from each treatment. Chimerism was confirmed in two putative pigmentation chimeras and in four piglets without overt signs of chimerism. The low percentage of injected embryos that yielded a chimera and the small contribution by EG cells to development of each confirmed chimera indicated that procedural changes in how EG cells were combined with host embryos were unsuccessful in increasing the likelihood that porcine EG cells will participate in embryonic development. Alternatively, our results suggested that improvements are needed in EG cell isolation and culture procedures to ensure in vitro maintenance of EG cell developmental capacity.

Animals↗
PubMed1999

Tolerance induction permits the development of graft-versus-host disease: donor-mediated attack following small bowel transplantation in mixed chimeras.

The induction of tolerance to organ allografts would eliminate acute and chronic rejection as well as the need for nonspecific immunosuppression. We have shown that tolerance induced through the creation of mixed allogeneic bone marrow chimeras allows for the long-term engraftment of cardiac and small bowel allografts across strong multiple major histocompatibility barriers. The possibility that tolerance might render the host susceptible to graft-versus-host disease (GVHD) has not been investigated in this or other models of tolerance. To test this possibility chimeras were created by transplantation of T-cell depleted ACI and Lewis bone marrow into lethally irradiated Lewis rats. Chimerism was determined post bone marrow transplant (BMTx) by flow cytometry of lymphocytes from reconstituted animals. ACI/Lew chimeras (ALC), Lewis/ACI F1 (LACF1), and Lewis (LEW) rats all received heterotopic ACI vascularized small bowel grafts. A second group of chimeras received small bowel grafts from ACI rats pretreated with low dose irradiation to eliminate T-cells from the graft. LEW-->LEW small bowel isografts were also performed. Animals were examined for evidence of GVHD by clinical signs and histologic examination of biopsied tissues. GVHD was quantified using the popliteal lymph node enlargement assay. All LACF1 rats developed severe lethal GVHD following ACI small bowel transplant. Bone marrow chimeras, ALC (n = 6), developed fatal GVHD in a similar fashion after receiving a small bowel transplant. LEW-->LEW isografts and chimeras receiving bowel from irradiated ACI rats survived long term without GVHD while ACI-->LEW allogeneic transplants all underwent acute rejection. GVHD or its absence was confirmed histologically. Popliteal lymph node enlargement indices reflected the presence of GVHD in the chimeras (1.87) and LACF1 (5.4) receiving allografts, but not in isografts or chimeras receiving irradiated allogeneic transplants. Analysis of cytokines in the tongues of rats undergoing GVHD showed elaboration of Th1 type proinflammatory cytokines which was not seen in isografted rats or rats receiving preirradiated small bowel. These results demonstrate that tolerance induction through mixed chimerism results in susceptibility to small bowel induced GVHD. Preirradiating the donor bowel prior to SBTx can prevent GVHD.

Animals↗
PubMed2000

Significant MLR but not CTL responses against recipient antigens generated in T cells from bone marrow chimeras recovered from acute GVHD.

Lethally irradiated AKR mice received BMT from H-2D and minor lymphocyte stimulatory (Mls)-1 disparate B10.A mice. No GVHD signs were detected in AKR recipients of T cell-depleted BM cells (1 x 10(7)) alone ([B10.A --> AKR] T-). When B10.A splenic T cells (1 x 10(5)) were injected in addition to T cell-depleted BM cells ([B10.A --> AKR] T+), overt GVHD was observed. [B10.A --> AKR] T+ chimeras recovered from the GVHD 8 weeks after BMT. In T cells from these [B10.A --> AKR] T+ chimeras, a substantial population of Mls-1a-reactive Vbeta6+ T cells was present, whereas the Vbeta6+ cells were deleted in [B10.A --> AKR] T- chimeras. T cells from [B10.A --> AKR] T+ chimeras showed considerable MLR but no CTL response against AKR cells (split tolerance). Upon stimulation with AKR stimulators or anti-CD3 MoAb, T cells from [B10.A --> AKR] T+ chimeras produced significantly more IL-4 but significantly less IFN-gamma compared with those from [B10.A --> AKR] T- chimeras or unmanipulated B10.A mice. The serum level of IgG1 in [B10.A --> AKR] T+ chimeras was also significantly higher than that in [B10.A --> AKR] T- or B10.A mice. The present findings suggest that the split tolerance observed in BMT chimeras recovered from GVHD is attributable to the Th2 dominant state.

Acute Disease↗
PubMed1985

Assessment of immunocompetence by limiting dilution analysis in long-term T cell depletion chimeras transplanted across the MHC barrier.

Chimeras were generated in a system in which donor C57BL/6 bone marrow plus spleen cells were T-cell-depleted prior to transplantation into lethally irradiated DBA/2 recipients. This protocol permits donor lymphohematopoietic engraftment and protects transplanted mice from development of lethal GVHD. The frequencies of alloantigen-specific cytotoxic T cells (CTL) and/or CTL precursors (CTL-P) in the chimera spleens were determined by limiting dilution analysis. This identified a small population of host-reactive CTL-P. The presence of host-reactive CTL-P in the absence of detectable anti-host immune response raises questions concerning the maintenance of the tolerant state in chimeras. Using mixtures of chimera and normal C57BL/6 splenocytes we found no evidence by limiting-dilution analysis for regulatory cells capable of dampening antihost immune reactivity in chimera spleens. We next measured the frequency of third-party-reactive CTL-P in chimeras. Chimeras displayed low CTL-P frequency by the 30th day posttransplant, which increased 15-21-fold over a five-month interval. Interestingly, both chimeric and irradiated syngeneic reconstituted control mice recovered anti-third-party CTL-P at a similar rate, but CTL-P levels never reached those measured in normal unirradiated control mice, suggesting that the radiation regimen has a long-lasting influence on host immunocompetence. In concomitant experiments we measured third-party CTL generation in MLC. Our findings suggest that measurement of CTL generation in MLC may be a less sensitive assessment of immunocompetence than LDA analysis. Our data also suggest that irradiated T-cell-depleted chimeras may suffer prolonged immunologic deficiencies based on reduced frequencies of alloreactive CTL-P.

Animals↗
PubMed2003

Adoptive immunotherapy against kidney targets in dog-leukocyte antigen-identical mixed hematopoietic canine chimeras.

BACKGROUND: Stable mixed-donor-host-hematopoietic chimerism can serve as a platform for adoptive immunotherapy. Infusions of donor lymphocytes (DLI) sensitized against hematopoietic cells converted mixed hematopoietic into full-donor chimerism in dog-leukocyte antigen (DLA)-identical littermates. Whether sensitization against tissue of solid organs leads to organ-specific immunity that can be transferred by DLI was unknown and was investigated in these experiments using the kidney as target. METHODS: DLA-identical recipients with established stable mixed-donor-host-hematopoietic chimerism were used. In five pairs, hematopoietic stem-cell transplant (HSCT) donors were sensitized by kidney transplantation from the respective chimeras. In a second group, five HSCT donors received vaccinations that were generated from kidney cells of the respective mixed chimeras. Twenty-eight days after sensitization, DLI were administered to the mixed-hematopoietic chimeras. RESULTS: All HSCT donors rejected their kidney grafts from their mixed-chimeric recipients within 22 to 45 days. DLI caused no sustained graft-versus-kidney effects in the mixed-chimeric recipients. However, DLI donors sensitized by kidney transplantation converted 4 of 5 mixed chimeras into virtually complete (>95%) donor-type chimeras, compared with 1 of 5 mixed chimeras given DLI by vaccination from sensitized donors. CONCLUSION: Although DLA-identical kidney grafts from mixed-hematopoietic chimeras were readily rejected by their HSCT donors, subsequent transfusions of sensitized-donor lymphocytes into mixed chimeras converted mixed to all-donor chimerism but failed to induce graft-versus-kidney effects. Vaccination strategies in lieu of kidney grafts failed to convert mixed chimerism.

Animals↗
PubMed2004

Effect of IL-12 and soluble IL-4 receptor on the herpesvirus infection in human SCID chimeras whose Th2 cells predominate.

Th2 cytokines, commonly detected in burn patients, have been shown as inhibitors for the generation of Th1 cells that are essential for the host's resistance against herpes simplex virus type 1 (HSV-1) infection. In this study, the possibility of immunological treatment through the regulation of Th1/Th2 responses was examined in two kinds of human severe combined immunodeficiency (SCID) chimera models reflecting human immune functions. SCID mice injected with a mixture of PBMC from a healthy donor and Th2 cells experimentally generated from the same healthy PBMC (Th2 SCID chimeras) were more susceptible to HSV-1 infection when compared with SCID mice injected with healthy donor PBMC (healthy SCID chimeras). When Th2 SCID chimeras were individually treated with human IL-12 (hIL-12) or human soluble IL-4 receptor (hsIL-4R), hIFN-gamma was not produced in their sera after antihuman CD3 mAb stimulation. However, hIFN-gamma production in sera of Th2 SCID chimeras treated with the combination therapy of hIL-12 and hsIL-4R was recovered at levels observed in healthy SCID chimeras. When Th2 SCID chimeras infected with HSV-1 were treated with saline, hIL-12, hsIL-4R or a combination of hIL-12 and hsIL-4R, 13%, 13%, 25% or 100% of them survived, respectively. Also, Th1 responses (hIFN-gamma production) were demonstrated in Th2 SCID chimeras that became resistant against HSV-1 infection after the combination treatment. These results suggest that individuals whose Th2 cells predominated may be immunologically controlled by the combination treatment between a Th1 response inducer and a Th2 response inhibitor.

Animals↗
PubMed1992

Studies on avian spinal cord chimeras. I. Neurological and histological manifestations.

Spinal cord chimeras were produced by replacing a small fragment of neural tube of a 2-day-old White Leghorn chicken embryo with a similar fragment from a Japanese quail embryo. The embryo mortality was 61%, and 72% of hatched birds were 'cripples' and had to be sacrificed within 5 days after hatching. Forty-nine chimeras, 10.9% of the total number of operated embryos, were alive for more than 3 weeks. For at least 17 days after hatching, all birds behaved like normal chicks, and the grey quail-like feathers were the only manifestations of their chimerism. Initial neurological symptoms of unsteady walking and drooping of the wings were noted in all birds except for 1 that died an accidental death before it became sick. Advanced symptoms characterized by paralysis of the legs forcing the bird to lie on its side were noted in 40 birds. The chimeras could be divided into two groups, each consisting of 24 birds. The short-survival (SS) chimeras of the first group became terminally ill and had to be sacrificed within 3 months. The long-survival (LS) chimeras of the second group showed more protracted disease, in that only 16 of them showed symptoms of the advanced disease, and the majority showed partial or complete recovery. Ten of the LS birds were kept alive for more than 8 months. Furthermore, many LS chimeras lost their grey feathers. The hallmarks of neurohistological manifestations were mononuclear cell infiltrates, demyelinization with preservation of axons and scar formation. These lesions were restricted to the quail fragment of the spinal cord except for 2 birds in which distant cellular infiltrates were observed. Direct immunofluorescence tests for chicken IgG were positive in spinal cords of most SS chimeras but only of some LS chimeras.

Animals↗
PubMed2002

Donor lymphocyte infusions mediate superior graft-versus-leukemia effects in mixed compared to fully allogeneic chimeras: a critical role for host antigen-presenting cells.

In mice, donor leukocyte infusion (DLI) given to established mixed allogeneic chimeras can mediate powerful graft-versus-host (GVH) reactions confined to the lymphohematopoietic system without inducing graft-versus-host disease (GVHD). In a clinical trial attempting to capture this approach to achieve graft-versus-leukemia/lymphoma (GVL) effects without GVHD, we have observed surprisingly powerful antitumor effects of DLI in patients achieving mixed chimerism after nonmyeloablative bone marrow transplantation. This observation led us to hypothesize that host antigen-presenting cells in mixed chimeras might be required to optimally present recipient antigens to the donor lymphocytes, leading to maximal graft-versus-tumor effects. To test this hypothesis, we established mixed and fully allogeneic hematopoietic chimeras in B6 mice and evaluated the effect of DLI on EL4 T-cell lymphoma. DLI administration to mixed chimeras produced dramatically improved leukemia-free survival compared to administration of DLI to full donor chimeras. DLI also converted mixed chimeras to full chimeras without causing GVHD. The magnitude of the GVL effect was dependent on the level of major histocompatibility complex class I expression on recipient hematopoietic cells in mixed chimeras. Thus, the induction of mixed chimerism followed by delayed DLI provides an approach to inhibiting GVHD that optimizes GVL effects.

Animals↗
PubMed1990

All-or-none craniorachischisis in Loop-tail mutant mouse chimeras.

Mouse embryos homozygous for the mutant gene Loop-tail (Lp) are characterized by craniorachischisis, an open neural tube extending from the midbrain to the tail. In the present study, experimental chimeric mice containing mixtures of genetically mutant (from Lp/+ x Lp/+ matings) and genetically normal cells were produced. Our aim was to determine whether a 'rescue,' phenotypic gradient, or intermediate expression (i.e. alternating areas of open and closed neural tube) would be observed in these chimeras. We report our analyses of Loop-tail mutant chimeras (n = 82) by gross examination, progeny testing and quantitative analysis of glucose phosphate isomerase (GPI) isozyme levels. An all-or-none craniorachischisis in Loop-tail mutant chimeras was observed. Two multicolored adult chimeras, without any gross evidence of a neural tube defect, were shown to be homozygous Loop-tail chimeras (Lp/Lp in equilibrium +/+) by progeny testing. These results indicate that the normal phenotype can be expressed in the presence of mutant cells. Conversely, six neonates with craniorachischisis were shown to be chimeras by GPI analyses. These results show that the full mutant phenotype can be expressed even when one-third to one-half of the cells are genotypically wild-type. This study did not determine which tissue is primarily responsible for the defective neurulation in this mutant, but suggests that a 'threshold' mechanism underlies the Loop-tail mutant phenotype. In some chimeras that threshold is not reached and the neural tube remains open, whereas in other chimeras the threshold is reached and the neural tube closes completely.

Animals↗
PubMed1982

Interspecific chimeras in mammals: a new experimental system.

The first viable interspecific chimeras in mammals have been made by mixing embryonic cells from two species of mouse, Mus musculus and Mus caroli. These chimeras resemble intraspecific chimeras in M. musculus in their patterns of mosaicism. They provide an interesting experimental system for studying interactions between cells of the two species. Three separate but related areas of investigation utilizing these chimeras are described. 1) In situ DNA-DNA hybridization using a cloned repetitive DNa sequence from M. musculus has enabled M. caroli and M. musculus cells to be distinguished in bone marrow spreads from chimeras. Further refinement of this technique should allow use of this in situ marker system for detailed analysis of cell distribution in chimeras. Such a ubiquitous marker system is not yet available in M. musculus. 2) Breeding interspecific chimeras has increased production of interspecific hybrids, which are very useful for studies of genetic interactions between the two species. 3) Mus caroli embryonic cells can survive in the M. musculus uterus in a chimera, although M. caroli embryos alone die around d 11 to 16 of pregnancy in M. musculus. Investigation of this phenomenon has implicated immune effector mechanisms in death of M. caroli embryos and has revealed the importance of trophoblast genotype for survival of foreign cells in the uterine environment.

Animals↗