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PubMed1997

Influence of perceptual and semantic conflicts between the two halves of chimeric stimuli on the expression of visuo-spatial neglect.

We investigated how perceptual and semantic relationships between the left and right half of chimeric stimuli influence overt and covert visual processing by asking eight right brain damaged (RBD) patients with hemispatial neglect to identify complete, half-, and chimeric drawings. Chimeric stimuli belonged in one of four categories defined according to the perceptual and semantic relatedness between the two compounding hemi-figures. Thus, the hemi-figures could be related both perceptually and semantically, only perceptually, only semantically, or neither perceptually nor semantically. Although patients often appeared to base their report on the right part of the chimerics, the number of errors was minimal when conflicts between the two hemi-figures were maximal. Moreover, perceptual conflicts, which mainly affect the perception of the shape, appeared to influence the performance more than semantic conflicts. Since the analysis of shape incongruency is probably accomplished at early levels of information processing, the result suggests that preattentive analysis is largely spared in the experimental patients and that, in our task, bottom-up factors more than top-down factors modulate the expression of left neglect.

Aged↗
PubMed1995

Alterations of the interleukin-4 pathway in production of tolerance by mixed hematopoietic chimerism.

BACKGROUND: The induction of specific tolerance could prevent acute and chronic rejection, as well as immunosuppressive complications, in recipients of vascularized organ allografts. Mixed hematopoietic chimerism is one approach to allogeneic tolerance. In these studies we examined whether mixed chimerism can confer tolerance to heart allografts across major and minor histocompatiblity barriers. We also examined the transcription of cytokine genes within the allografts of tolerance animals and in cell culture. METHODS: Adult Lewis rats were lethally irradiated and reconstituted with a mixture of 50 x 10(6) T-cell depleted bone marrow cells. Chimeric animals received heterotopic donor strain and third-party heart allografts and were assessed daily for rejection. Another set of chimeras received heart allografts that were examined at varying time points for transcription of cytokine genes by reverse-transcriptase polymerase chain reaction. RESULTS: Median graft survival in control animals was 6 days. Graft survival in 11 mixed chimeras ranged from more than 165 to more than 274 days (p < 0.001), and no episode of rejection or graft-versus-host disease was observed. Examination of cytokine transcriptions revealed dramatic alterations in interleukin-4 transcription in vivo and in vitro. CONCLUSIONS: Alterations in cytokine gene transcription are descriptive of tolerance in this model. Mixed chimerism confers long-term unresponsiveness to heart allografts across major and minor histocompatibility barriers with desirable features for clinical application.

Animals↗
PubMed2003

Chimeric flaviviruses: novel vaccines against dengue fever, tick-borne encephalitis, and Japanese encephalitis.

Many arthropod-borne flaviviruses are important human pathogens responsible for diverse illnesses, including YF, JE, TBE, and dengue. Live, attenuated vaccines have afforded the most effective and economical means of prevention and control, as illustrated by YF 17D and JE SA14-14-2 vaccines. Recent advances in recombinant DNA technology have made it possible to explore a novel approach for developing live attenuated flavivirus vaccines against other flaviviruses. Full-length cDNA clones allow construction of infectious virus bearing attenuating mutations or deletions incorporated in the viral genome. It is also possible to create chimeric flaviviruses in which the structural protein genes for the target antigens of a flavivirus are replaced by the corresponding genes of another flavivirus. By combining these molecular techniques, the DNA sequences of DEN4 strain 814669, DEN2 PDK-53 candidate vaccine and YF 17D vaccine have been used as the genetic backbone to construct chimeric flaviviruses with the required attenuation phenotype and expression of the target antigens. Encouraging results from preclinical and clinical studies have shown that several chimeric flavivirus vaccines have the safety profile and satisfactory immunogenicity and protective efficacy to warrant further evaluation in humans. The chimeric flavivirus strategy has led to the rapid development of novel live-attenuated vaccines against dengue, TBE, JE, and West Nile viruses.

Amino Acid Sequence↗
PubMed1997

Production of a mouse/human chimeric IgE monoclonal antibody to the house dust mite allergen Der p 2 and its use for the absolute quantification of allergen-specific IgE.

A chimeric human IgE monoclonal antibody was developed against the house dust mite allergen Der p 2. This chimeric antibody (hIgE-Dp2A) was composed of the heavy-chain variable domains and light chains of the original murine monoclonal antibody retaining its binding characteristics, whereas the heavy-chain constant domains were exchanged with the human IgE heavy chain. The chimeric IgE expression level was IgE 600 IU/ml (1 IU = 2.4 ng/ml). The binding of the chimeric hIgE-Dp2A to mite extract was indistinguishable from that of the original mouse monoclonal antibody. Parallel dose-response curves were found when the binding of hIgE-Dp2A to mite extract and anti-IgE coupled to sepharose were compared. Binding levels were not identical; however, hIgE-Dp2A bound significantly better to the mite-extract sepharose. This result indicates that the commonly used anti-IgE on solid phase calibration systems may lead to an overestimation of the amount of allergen-specific IgE present in the serum sample. The less efficient binding of the detector anti-IgE in case of the anti-IgE sepharose is likely to be because of the occupation of epitopes of the IgE by the sepharose-bound anti-IgE. Dose-response curves of serial dilutions of patient samples were parallel with the hIgE-Dp2A dose-response curve, which indicates that hIgE-Dp2A behaves like natural IgE antibodies in binding to allergen coupled to solid phase. This antibody is well suited for use as a reference reagent in the RAST and enables the expression of the amount of allergen-specific IgE present in a patient sample in absolute amounts.

Allergens↗
PubMed1994

Bone marrow augmentation of donor-cell chimerism in kidney, liver, heart, and pancreas islet transplantation.

We have previously postulated that donor cell chimerism in organ transplantation is needed to attain a tolerant state. Here we show that donor cell chimerism can be augmented in organ recipients if they are infused perioperatively with 3 x 10(8) per kg of unmodified donor bone marrow cells and are kept on a conventional immunosuppressive regimen of tacrolimus (FK506) and prednisolone. 36 patients took part, of whom the first 18 patients have good transplanted kidney (n = 10), liver (n = 7), and heart (n = 7) function when followed up between 4 and 16 months. All patients are well. We found persistent multilineage leucocyte chimerism in blood of 17 recipients by flow cytometry and PCR techniques to detect donor alleles or Y chromosomes in female recipients of male organs. The use of the 5-antigben HLA matched same sex donor precluded detection of chimerism in one patient.

Adult↗
PubMed2002

Morphological consequences for multi-partner chimerism in Botrylloides, a colonial urochordate.

Studies on multi-partner chimeras (MC) of the colonial urochordate Botryllus schlosseri have revealed that these chimeras form more stable and vigorous entities than bi-partner chimeras (BC). This outcome has been further studied here on another botryllid species. Botrylloides leachi subpopulation 1, by analysing the morphological consequences of BC, chimeras comprising three partners, tri-chimeras (TC) and chimeras comprising six partners each, hexa-chimeras (HC). For each chimerical type, five different genotypic combinations with three replicates per combination were established. Chimeras were observed for up to 10 months, at which point, all had died. While life spans of BC, TC and HC were the same, the average maximum sizes of HC were higher resulting from more than three times greater daily growth rate. BC and TC reached a maximal chimeric size at a much earlier age. Some morphological resorptions were also expressed differently in HC as compared to BC. When comparing chimerical parameters of bi- vs. multi-chimerism between Botryllus and Botrylloides, these two genera differ in nine out of 13 characteristics tested. However, it seems that irrespective to the species studied and the different characteristics expressed, MC in botryllid ascidians is a commonly developed phenomenon shaped by evolutionary pressures that interact on a 'group' level instead of each individual partner. MC reveal modified entities in which contradicting intraspecific interactions are alleviated.

Animals↗
PubMed1997

Tuftsin-THF-gamma 2 chimeric peptides: potential novel immunomodulators.

Synthesis of two chimeric peptides composed of tuftsin and thymic humoral factor-gamma 2 (THF-gamma 2) conjugates was accomplished. Our goal was the generation of novel immunomodulators. Initially, we demonstrate an IL-6 inducing activity of the phagocytic cells stimulant, tuftsin, on murine macrophages. This activity was documented only in the presence of antigen, either KLH or lysozyme. The augmentation was dose dependent, with optimal activity at a concentration of 200 and 20 nM, respectively. The chimeric peptides, either H2N-tuftsin-THF-gamma 2-OH or H2N-THF-gamma 2-tuftsin-OH, were also evaluated in the IL-6 system in the presence of the more potent antigen, KLH. The IL-6 inducing effect was maintained, although maximal activity appeared only at a concentration an order of magnitude greater than that of tuftsin. The chimeric peptides were further tested in an assay evaluating enhancement in murine bone marrow myeloid colony formation, a system in which THF-gamma 2, a T cell stimulant, has an established beneficial effect. The compounds were found to be inactive at the 25-200 ng/ml (14-112 nM) concentration range evaluated. Finally, the chimeric peptides were tested in a combined macrophages-T cells assay, i.e. antigen presentation, in which H2N-tuftsin-THF-gamma 2-OH was found to be more active than either parent peptide, thus representing a possible therapeutic agent.

Adjuvants, Immunologic↗
PubMed1999

Easy assessment of ES cell clone potency for chimeric development and germ-line competency by an optimized aggregation method.

Production of germ-line competent chimeric mice from embryonic stem (ES) cells is an inevitable step in establishing gene-manipulated mouse lineages. A common method used for creating chimeric mice is the injection of ES cells into the blastocoelic cavity (blastocyst injection). The aggregation method is an alternative way to introduce ES cells to the host embryo which is less difficult than blastocyst injection. Here we re-examined the condition of embryo-ES cell coculture on the aggregation method and found improvement of germ-line competent chimeric production by a simple modification of the coculture medium. Moreover, R1 ES cell and its 10 gene-manipulated subclones were tested by this method. Although all ES cell clones showed good morphology and a normal karyotype, the efficiency of chimeric development and germ-line transmission varied among clones and were classified into three grades according to germ-line competency. In the first group (class A), both the incidence of chimera with high ES cell contribution and the rate of germ-line transmission were fairly high. Germ-line competent chimeras were obtained but with rather low efficiency in the second group (class B), while another group (class C) showed an absence of high ES cell-contributed chimeras and no germ-line transmission. These results suggest the usefulness of this modified aggregation method to predict the potency of ES cell clones for germ-line competency.

Animals↗
PubMed2000

Chimeric swine vesicular disease viruses produced by fusion PCR: a new method for epitope mapping.

A new method of epitope mapping based on chimeric swine vesicular disease (SVD) viruses produced by fusion PCR (polymerase chain reaction). Seven out of 16 neutralising and non-neutralising newly produced monoclonal antibodies (MAbs) discriminated between SVD isolate ITL/1/66 and NET/1/92. Using fusion PCR eight chimeric viruses were produced containing different supplementary pieces of the P1 region of both parent strains. Using these chimeric viruses we were able to map the epitope regions recognised by these seven neutralising and non-neutralising Mabs. This new method, using chimeric viruses produced by fusion PCR, is particularly valuable for the epitope mapping of non-neutralising MAbs.

Animals↗
PubMed2002

Construction of yellow fever-influenza A chimeric virus particles.

In order to obtain a better understanding of the functional mechanisms involved in the fusogenesis of enveloped viruses, the influenza A (X31) and the yellow fever (17DD) virus particles were used to construct a chimeric structure based on their distinct pH requirements for fusion, and the distinct malleability of their nucleocapsids. The malleable nucleocapsid of the influenza A virus particle is characterized by a pleomorphic configuration when observed by electron microscopy. A heat inactivated preparation of X31 virus was used as a lectin to interact with the sialic acid domains present in the 17DD virus envelope. The E spikes of 17DD virus were induced to promote fusion of both envelopes, creating a double genome enveloped structure, the chimeric yellow fever-influenza A virus particle. These chimeric viral particles, originally denominated 'partículas virais quiméricas' (PVQ), were characterized by their infectious capacity for different biological systems. Cell inoculation with PVQ resulted in viral products that showed similar characteristics to those obtained after 17DD virus infections. Our findings open new opportunities towards the understanding of both virus particles and aspects of cellular physiologic quality control. The yellow fever-influenza A chimeric particles, by means of their hybrid composition, should be a valuable tool in the study of cell biology and the function of viral components.

Animals↗
PubMed2004

Anxiety-related behaviour in C57BL/6 <--> BALB/c chimeric mice.

In a previous study on anxiety-related behaviours of the genetically and behaviourally distant inbred mouse strains C57BL/6 and BALB/c using the Elevated plus-maze (EPM) and Open-field (OF) apparatuses, we identified a number of variables, the factorial scores of which were grouped by principal component analysis (PCA) into factors specifically describing each inbred strain. We have now studied the effect of C57BL/6 and BALB/c haploid sets of genes on this behaviour by comparing EPM and OF variables of C57BL/6 and BALB/c versus C57BL/6 x BALB/c F1 hybrids (B6CBF1) and chimeric C57BL/6 x BALB/c (CHIM) mice. CHIM mice were made by embryo aggregation and the chimerism degree of their brain was inferred from coat black/white distribution. Discriminant analysis of EPM and OF factorial scores of C57BL/6, BALB/c and CHIM mice showed that CHIM mice with an exceeding (> or =80%) C57BL/6 or BALB/c coat component had behaviours similar to those of the predominant strain, whereas CHIM mice with intermediate chimerism differed from both inbred strains. Additional MANOVA analysis showed that the anxiety behaviour of CHIM mice with intermediate chimerism was similar to that of B6CBF1 mice as for factors not describing the inbred strains, including a motor activity mostly limited to protected areas, with attempts to approach the anxiogenic areas while processing/storing the external information. We conclude that the balanced presence of both C57BL/6 and BALB/c genetic backgrounds, either when carried by the same cell or by different cells, gives rise to a novel stress coping strategy described by factors different from those of the inbred strains.

Animals↗
PubMed2000

Hyperactivity and interactions of a chimeric myristoryl-ACP thioesterase from the lux system of luminescent bacteria.

A chimeric myristoyl-ACP thioesterase with much higher catalytic efficiency than the parental enzymes has been generated by ligating the N-terminal half of the lux-specific thioesterase (LuxD) from Photobacterium phosphoreum with the C-terminal half of LuxD from Vibrio harveyi. The LuxD chimera had the same rate-limiting step and specificity, but cleaved esters and thioesters over eight times faster than the native enzymes. LuxD, along with acyl-protein synthetase (LuxE) and reductase (LuxC), comprise a multienzyme complex channeling activated fatty acids into the aldehyde substrate for the bacterial bioluminescence reaction. As P. phosphoreum LuxD and LuxE modulate each of their respective activities, the effects of mixing V. harveyi and the chimeric LuxD with P. phosphoreum LuxE were investigated. The chimeric LuxD stimulated acylation of LuxE to the same extent as V. harveyi LuxD, but to a lower level than that caused by P. phosphoreum LuxD. Conversely, P. phosphoreum LuxE stimulated the thioesterase activity of V. harveyi LuxD by 30% and the chimeric LuxD by 20% while the activity of P. phosphoreum LuxD was increased by over 140%. These results show that the stimulatory effects are unrelated to the level of thioesterase activity and indicate that the carboxyl terminal region of LuxD interacts with LuxE and causes a conformational change.

Acyltransferases↗
PubMed2000

Chimeric classical swine fever viruses containing envelope protein E(RNS) or E2 of bovine viral diarrhoea virus protect pigs against challenge with CSFV and induce a distinguishable antibody response.

Three chimeric classical swine fever virus (CSFV)/bovine viral diarrhoea virus (BVDV) full-length DNA copies were constructed, based on the infectious DNA copy of the CSFV vaccine strain C. The antigenic region of E2 and/or the complete E(RNS) gene were replaced by the analogous sequence of BVDV II strain 5250. Viable chimeric virus Flc11, in which E(RNS) was replaced, was directly recovered from supernatant of SK6.T7 cells transfected with full-length DNA. Viable chimeric virus Flc9, in which E2 was replaced, resulted in recovery of virus only when SK6.T7 transfected cells were maintained for several passages. However, no virus could be recovered after replacement of both E(RNS) and E2, even after 10 cell passages. Both Flc9 and Flc11 grow in swine kidney cells (SK6), stably maintain their heterologous BVDV sequences and, as assessed by monoclonal antibody typing and radio-immunoprecipitation assays, express their heterologous proteins. Flc9 showed a slower growth rate on SK6 cells than Flc11 and wild-type Flc2 virus. Replacement of E(RNS) or E2 of C-strain-based chimeric viruses did not alter cell tropism compared to wild-type C-strain virus for SK6 and FBE cells. Both Flc9 and Flc11 induced E2 or E(RNS) antibodies, which could be discriminated from those induced after wild-type virus infection, even after repeated vaccination. Furthermore, pigs were completely protected against a lethal CSFV challenge. These results indicate the feasibility of introduction of marker antigens in a live-attenuated marker C-strain vaccine for CSFV.

Amino Acid Sequence↗
PubMed1999

A chimeric protein comprised of bovine herpesvirus type 1 glycoprotein D and bovine interleukin-6 is secreted by yeast and possesses biological activities of both molecules.

Bovine herpesvirus type 1 (BHV-1) glycoprotein D (gD) engenders mucosal and systemic immunity and protects cattle from viral infection. Chimerization of cytokines with gD is being explored to confer intrinsic adjuvanticity on gD. Addition of the appropriate cytokine may convert gD into an antigen that specifically engenders protective mucosal immunity. Here DNA coding for the mature bovine interleukin-6 (IL-6) protein was fused through a synthetic glycine linker to the 3' end of DNA coding for the mature BHV-1 gD (tgD) external domain. It was cloned behind the yeast alpha prepro signal sequence and transfected into Pichia pastoris which secreted the chimeric protein (tgD-IL-6) as a 100 kDa molecule. This chimera combined the immunogenic properties of native gD and the in vitro biological activity of bovine IL-6 based on the following observations. A panel of BHV-1 gD-specific monoclonal antibodies recognizing five neutralizing epitopes on native gD reacted with tgD-IL-6. Sera from yeast tgD-IL-6-immunized mice neutralized BHV-1 infection in vitro. The chimeric protein enhanced total bovine immunoglobulin production 16-fold above tgD alone in pokeweed-stimulated bovine peripheral blood mononuclear cells (P < 0.05). This chimeric protein may be a potent mucosal immunogen.

Amino Acid Sequence↗
PubMed1999

A live attenuated chimeric recombinant parainfluenza virus (PIV) encoding the internal proteins of PIV type 3 and the surface glycoproteins of PIV type 1 induces complete resistance to PIV1 challenge and partial resistance to PIV3 challenge.

The recovery of wild type and attenuated human parainfluenza type 3 (PIV3) recombinant viruses has made possible a new strategy to rapidly generate a live-attenuated vaccine virus fof PIV1. We previously replaced the coding sequences for the hemagglutinin-neuraminidase (HN) and fusion (F) proteins of PIV3 with those of PIV1 in the PIV3 antigenomic cDNA. This was used to recover a fully-viable, recombinant chimeric PIV3-PIV1 virus, termed rPIV3-1, which bears the major protective antigens of PIV1 and is wild type-like with regard to growth in cell culture and in hamsters [Tao T, Durbin AP, Whitehead SS, Davoodi F, Collins PL, Murphy BR. Recovery of a fully viable chimeric human parainfluenza virus (PIV) type 3 in which the hemagglutinin-neuraminidase and fusion glycoprotein have been replaced by those of PIV type 1. J Virol 1998;72:2955-2961]. Here we report the recovery of a derivative of rPIV3-1 carrying the three temperature-sensitive and attenuating amino acid coding changes found in the L gene of the live-attenuated cp45 PIV3 candidate vaccine virus. This virus, termed rPIV3-1.cp45L, is temperature-sensitive with a shut-off temperature of 38 degrees C, which is similar to that of the recombinant rPIV3cp45L, which possesses the same three mutations. rPIV3-1.cp45L is attenuated in the respiratory tract of hamsters to the same extent as rPIV3cp45L. Infection of hamsters with rPIV3-1.cp45L generated a moderate level of hemagglutination-inhibiting antibodies against wild type PIV1 and induced complete resistance to challenge with wild type PIV1. This demonstrates that this novel attenuated chimeric virus is capable of inducing a highly effective immune response against PIV1. It confirms previous observations that the surface glycoproteins of parainfluenza viruses are sufficient to induce a high level of resistance to homologous virus challenge. Unexpectedly, infection with recombinant chimeric virus rPIV3-1.cp45L or rPIV3-1, each bearing the surface glycoprotein genes of PIV1 and the internal genes of PIV3, also induced a moderate level of resistance to replication of wild type PIV3 challenge virus. This indicates that the internal genes of PIV3 can independently induce protective immunity against PIV3 in rodents, albeit a lower level of resistance than that induced by the surface glycoproteins. Thus, a reverse genetics system for PIV3 has been used successfully to produce a live attenuated PIV1 vaccine candidate that is attenuated and protective in experimental infection in hamsters.

Animals↗
PubMed2000

A live attenuated recombinant chimeric parainfluenza virus (PIV) candidate vaccine containing the hemagglutinin-neuraminidase and fusion glycoproteins of PIV1 and the remaining proteins from PIV3 induces resistance to PIV1 even in animals immune to PIV3.

Using a reverse genetics system for PIV3, we previously recovered recombinant chimeric PIV3-PIV1 virus bearing the major protective antigens of PIV1, the hemaglutinin-neuraminidase and fusion proteins, on a background of PIV3 genes bearing temperature sensitive (ts) and attenuating mutations in the L gene. Immunization of hamsters with this virus, designated rPIV3-1.cp45L, induced a high level of resistance to replication of wild type (wt) PIV1 and, surprisingly, also induced a moderate amount of restriction of the replication of PIV3 challenge virus. This suggested that some immunity is conferred by the internal PIV3 proteins shared by the two viruses. In the present study, we found that the immunity to PIV3 conferred by infection with rPIV3-1.cp45L is short-lived and completely disappeared four months after immunization, whereas resistance to replication of PIV3 induced by prior infection with PIV3 remains high even after an interval of four months. Since a live attenuated PIV1 vaccine such as the chimeric rPIV3-1.cp45L virus will likely be given to infants after a live attenuated PIV3 vaccine in a sequential immunization schedule, we examined the immunogenicity and efficacy of rPIV3-1.cp45L against PIV1 challenge in animals with and without prior immunity to PIV3. rPIV3-1.cp45L efficiently infected hamsters previously infected with wt or attenuated PIV3, but there was approximately a five-fold reduction in replication of rPIV3-1. cp45L virus in the PIV3-immune animals. This reduction in replication of rPIV3-1.cp45L in PIV3-immune animals was accompanied by a significant decrease in efficacy against PIV1 challenge. However, rPIV3-1.cp45L immunization of PIV3-immune animals induced a vigorous serum antibody response to PIV1 and reduced replication of PIV1 challenge virus 1000-fold in the lower respiratory tract and 25 to 200-fold in the upper respiratory tract. This study demonstrated that the recombinant chimeric rPIV3-1.cp45L candidate vaccine can induce immunity to PIV1 even in animals immune to PIV3. This establishes the feasibility of employing a sequential immunization schedule in which a recombinant chimeric rPIV3-1.cp45L vaccine is given following a live attenuated PIV3 vaccine.

Animals↗
PubMed2002

Adenovirus vectors containing chimeric type 5 and type 35 fiber proteins exhibit altered and expanded tropism and increase the size limit of foreign genes.

Adenovirus (Ad) fiber proteins are responsible for the initial attachment of the virion to the cell membrane. Most Ad vectors currently in use are based on the Ad type 5 (Ad5), which belong to subgroup C, and use the coxsackievirus and adenovirus receptors (CAR) as the initial receptor. Ad35, which belongs to subgroup B, recognizes unknown receptor(s) other than CAR. In this study, the feasibility of the Ad vector containing Ad5/35 chimeric fiber protein was examined in a wide variety of cell types, such as CAR-positive or -negative human tumor cells, rodent cells, and blood cells (a total of 20 cell types), and in mice in vivo. Transduction data suggested that the Ad vectors containing the Ad5/35 chimeric fiber protein exhibited altered and expanded tropism when compared with the Ad5-based vector. The chimeric vector also allows the packaging of larger foreign DNAs than the conventional Ad5-based vector, which can package approximately 8.1-8.2 kb of foreign DNA. The chimeric vector containing approximately 8.8 kb of foreign DNA was generated without affecting the viral growth rate and titer. These results suggested that inclusion of the Ad35 fiber protein into the Ad5-based vector could lead to an improved efficiency in gene therapy and in gene transfer experiments, especially for the cells lacking in sufficient CAR expression.

Adenoviridae↗
PubMedDate not supplied

Permanent acceptance of both cardiac and skin allografts using a mild conditioning regimen for the induction of stable mixed chimerism in mice.

Patients who are receiving an organ transplant nowadays are sentenced to the life-long administration of immunosuppressive drugs, which have serious side effects. The reliable induction of donor-specific tolerance therefore remains a major goal in organ transplantation. Previously, we have developed a sublethal, non-myeloablative murine model in which permanent mixed, multilineage chimerism and donor-specific tolerance are established. Our model involves engraftment of fully allogeneic T cell depleted donor bone marrow cells in low dose irradiated and anti-CD3 treated major histocompatibility complex (MHC)-disparate recipient mice. To investigate whether vascularized organ grafts are accepted in our model, we performed heterotopic heart transplantations in our mixed chimeric mice. Chimeric mice permanently accepted hearts from the bone marrow donor (>130 days) and rapidly rejected third party-type allografts (median survival time 9 days). Untreated control recipient mice rejected both donor- and third party-type allografts. In addition, mice that accepted their cardiac grafts, donor-specific acceptance of skin grafts was observed. In conclusion, the establishment of stable mixed chimerism with this low-toxicity regimen resulted in permanent donor-specific acceptance of vascularized organ as well as skin grafts across a full MHC barrier.

Animals↗