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PubMed2006

CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells.

Chimeric antigen receptors (CAR) combine an antigen-binding domain with a CD3-zeta signaling motif to redirect T-cell specificity to clinically important targets. First-generation CAR, such as the CD19-specific CAR (designated CD19R), may fail to fully engage genetically modified T cells because activation is initiated by antigen-dependent signaling through chimeric CD3-zeta, independent of costimulation through accessory molecules. We show that enforced expression of the full-length costimulatory molecule CD28 in CD8(+)CD19R(+)CD28(-) T cells can restore fully competent antigen-dependent T-cell activation upon binding CD19(+) targets expressing CD80/CD86. Thus, to provide costimulation to T cells through a CD19-specific CAR, independent of binding to CD80/CD86, we developed a second-generation CAR (designated CD19RCD28), which includes a modified chimeric CD28 signaling domain fused to chimeric CD3-zeta. CD19R(+) and CD19RCD28(+) CD8(+) T cells specifically lyse CD19(+) tumor cells. However, the CD19RCD28(+) CD8(+) T cells proliferate in absence of exogenous recombinant human interleukin-2, produce interleukin-2, propagate, and up-regulate antiapoptotic Bcl-X(L) after stimulation by CD19(+) tumor cells. For the first time, we show in vivo that adoptively transferred CD19RCD28(+) T cells show an improved persistence and antitumor effect compared with CD19R(+) T cells. These data imply that modifications to the CAR can result in improved therapeutic potential of CD19-specific T cells expressing this second-generation CAR.

Animals↗
PubMedDate not supplied

Absence of a relationship between the increased survival of skin grafts provoked by additional spleen transplantation and the detection of donor chimeric cells in rats.

The goal of this study was to examine the relationship between the effects of spleen transplantation on the acceptance of a skin allograft from the same donor and the detection of donor chimerism in recipient tissues. Male Sprague-Dawley rats and female Wistar rats were used as donors and recipients, respectively. Four experimental groups were established: group C: only skin grafting was performed; group S: recipients were splenectomized before skin grafting; group 1: skin grafts were performed immediately after splenectomy of recipients and spleen transplantation, and group 2: splenectomy of the recipients and spleen grafting were performed 48 h before skin grafting. All animals were sacrificed 14 weeks after surgery. The rate of acceptance of skin grafts was significantly higher in animals that received both skin and spleen transplantations than in group C (p = 0.03) or in group S (p = 0.04). Detection of donor chimeric cells was significantly more frequent in rats after spleen transplantation than in group C (p = 0.03). However, the detection of chimeric cells was not related to the acceptance of skin grafts. To conclude, the beneficial effect of spleen auxiliary transplantation on allograft survival was not related to the detection of long-term chimerism in the recipient's tissues.

Animals↗
PubMed2003

Chimeric T-cell receptors for the targeting of cancer cells.

Genetic engineering of human T lymphocytes to express tumor antigen-specific chimeric immune receptors is an attractive means for providing large numbers of effector cells for adoptive immunotherapy. Major mechanisms of tumor escape from immune recognition are efficiently bypassed. Although adoptive transfer of chimeric receptor-expressing peripheral blood-derived T lymphocytes has produced some anti-tumor activity in mice, the first clinical studies have revealed a disappointing lack of correlation between in vitro cytotoxicity and therapeutic efficacy. The most pertinent issue is that chimeric T cells fail to expand and rapidly lose their function in vivo. Potential strategies to enhance the therapeutic value of chimeric receptor-modified cells by preventing their functional inactivation in vivo are currently being investigated.

Adoptive Transfer↗
PubMed2005

Replication-competent chimeric hepatitis C virus subgenomic replicons.

OBJECTIVE: To utilize chimeric hepatitis C virus (HCV) replicons to select adaptive mutation(s) that allow replication of a genotype 1a replicon. METHODS: We used a genetic approach to gradually apply selective pressure by generating chimeric replicons through sequential replacement of nonstructural genes of a 1b replicon with genotype 1a sequences. RESULTS: A chimeric replicon containing a genotype 1a NS5A protein did not replicate in a transient assay, but could be used to establish stable cell lines using G418 selection. The cell lines contained a K1846T mutation in NS4B which functioned as an adaptive mutation that now allowed the chimera to replicate at levels similar to wild-type replicons. Similarly, replication of a 1a NS5A5B chimera was only observed after establishment of stable cell lines, even in the presence of the K1846T mutation. Sequence analysis of this cell line revealed an additional adaptive mutation of M1496L in NS3. Lastly, by including the K1846T mutation in a replicon that was entirely genotype 1a sequence, stable 1a cell lines could be established. CONCLUSION: These studies identify an NS4B adaptive mutation, K1846T, which allows establishment of a replication-competent 1a replicon and demonstrate the utility of this chimeric approach for establishing replicons for various HCV genotypes.

Amino Acid Substitution↗
PubMed1996

Chimeric rhinoviruses as tools for vaccine development and characterization of protein epitopes.

Chimeric human rhinoviruses (HRVs) have the potential to serve as vaccines against a wide variety of diseases. Such vaccines can be developed optimally by generating libraries of chimeric HRVs displaying immunogens from dangerous pathogens or tumor cells in many different conformations. Extremely large numbers of conformationally defined presentations of foreign epitopes can be produced efficiently by flanking transplanted epitopes with linkers, or adapters, of small segments of randomized amino acids. In addition, the individual residues of the immunogenic sequences can be encoded in proportion to their prevalence in databases, generating composite immunogens that function as mimotopes. The diversity of sequences and conformations improves the likelihood of generating immunologically valuable vaccine candidates. Chimeric viruses thus generated can be propagated and purified to select for viruses whose growth and physical stability are like those of wild-type HRV. Viruses containing a foreign epitope in antigenically relevant conformations can then be captured by immunoselection with neutralizing antibodies directed against the foreign pathogen. Using this approach, we have been able to generate HRV chimeras that present V3 loop sequences of the human immunodeficiency virus type 1 (HIV-1) in immunologically relevant conformations. Antisera directed against such chimeras can neutralize multiple strains of HIV-1 in cell culture, suggesting that the HRV14:HIV-1 chimeras may be presenting their V3 loop sequences in manners that mimic those of multiple strains of HIV. Immunologically interesting chimeras can be examined using X-ray crystallography to yield detailed information about the structures of chimeras with immunogenic epitopes. This information may lead to a greater understanding of key functional and structural elements of immunogenicity. The chimeric HRV system allows one to present virtually any protein epitope or mimitope thereof, identify viruses with immunological characteristics that mimic those of the foreign pathogen, and examine the structures of these immunogenic sequences at the atomic level.

Epitopes↗
PubMed1975

Single-born marmosets without hemopoietic chimerism: naturally occurring and induced.

Marmosets have a high frequency of fraternal twinning, and placental vascular anastomoses between the twin fetuses invariably lead to hemopoietic chimerism. The occasional finding of chimerism in single-born marmosets suggested that in a twin pregnancy one fetus had undergone resorption after contributing hemopoietic stem cells to its twin. In this study non-chimeric single-born marmosets were produced by fallopian tube ligation or surgical relocation of one ovary in breeding females. Further, in an examination of hemopoietic cells from over 50 single-born young from nonoperated females, chimerism occurred less frequently than what one would expect if resorption of a co-twin had occurred after a functional anastomosis had been established.

Age Factors↗
PubMed1995

Noninvasive localization of experimental atherosclerotic lesions with mouse/human chimeric Z2D3 F(ab')2 specific for the proliferating smooth muscle cells of human atheroma. Imaging with conventional and negative charge-modified antibody fragments.

BACKGROUND: A murine monoclonal antibody designated Z2D3 (IgM) generated against homogenized human atherosclerotic plaques was demonstrated to be highly specific for proliferating smooth muscle cells. The primary clone subsequently was genetically engineered to provide a mouse/human chimeric antibody with human IgG1 constant region expressed in a rat myeloma cell line. The resulting Z2D3-73.30 chimeric retained the immunoreactivity relative to the parent Z2D3-IgM and was pepsin-digested to yield F(ab')2. 111In-labeled chimeric Z2D3 F(ab')2 was then used for noninvasive imaging of experimental atherosclerotic lesions. To improve the imaging characteristics, we modified chimeric Z2D3 F(ab')2 fragments to carry a high negative charge. Improved visualization of targets with 111In-labeled, negatively charged, polymer-modified antibodies most probably is the result of faster blood clearance and a decrease in nontarget background activity. METHODS AND RESULTS: Experimental atherosclerotic lesions were induced in rabbits by deendothelialization of the infradiaphragmatic aorta followed by a 6% peanut oil-2% cholesterol diet. After 12 weeks, localization of the conventionally labeled 111In-Z2D3 F(ab')2 (24 Mbq [650 microCi]/500 to 750 micrograms) (n = 4) was compared with 111In-labeled, negatively charged, polymer-modified Z2D3 F(ab')2 (24 Mbq [650 microCi]/25 to 50 micrograms) in eight atherosclerotic rabbits. Three control rabbits also received radiolabeled polymer-modified Z2D3. Ten rabbits with atherosclerotic lesions received 111In-labeled nonspecific human IgG1 F(ab')2 with (n = 6) or without (n = 4) negative charge modification. Atherosclerotic lesions were visualized in all rabbits with the conventional Z2D3 F(ab')2 at 48 hours. However, unequivocal lesion visualization was possible at 24 hours only with negatively charged, polymer-modified Z2D3 F(ab')2. Quantitative uptake of F(ab')2 fragments was essentially determined by the presence of atherosclerotic lesions (F1.37 = 69.8; P < .0001) and the specificity of the antibody (F1.37 = 36.6; P < .0001). Uptake of the conventional Z2D3 in atherosclerotic lesions (mean +/- SEM percent injected dose per gram, 0.112 +/- 0.024%) was six times higher than background activity in the normal aortic segments (nondenuded thoracic aorta; mean percent injected dose per gram, 0.019 +/- 0.003%). Uptake of the conventional Z2D3 was also significantly higher than that of nonspecific human IgG1 F(ab')2 (0.027 +/- 0.004%). Specific uptake of the conventional Z2D3 in the lesions was comparable to the charge-modified Z2D3 uptake (0.084 +/- 0.017; P = .20). Uptake of negative charge-modified Z2D3 in the lesions was significantly higher than in the corresponding background activity in normal thoracic aorta (0.021 +/- 0.002). Uptake of negative charge-modified Z2D3 F(ab')2 in the lesions was higher than the uptake of negative charge-modified nonspecific IgG1 F(ab')2 (0.020 +/- 0.002) in the lesions. Uptake of charge-modified Z2D3 in the atherosclerotic lesions was also significantly higher than the corresponding regions of the aorta of the control rabbits (0.017 +/- 0.002; F1.18 = 27.9; P = .0001). There was, however, no difference in the specific lesion uptake of negative charge-modified Z2D3 at 24 hours (0.079 +/- 0.014) and 48 hours (0.084 +/- 0.0017; P = .99) after intravenous administration. Nontarget organ activities were lower with negative charge-modified 111In-labeled Z2D3 F(ab')2 than with the conventional Z2D3 F(ab')2. Mean kidney activity was fourfold less with the modified (0.45 +/- 0.06) than with the conventionally radiolabeled (1.67 +/- 0.264; P = .001) Z2D3 F(ab')2.

Animals↗
PubMed2003

Hematopoietic chimerism and central tolerance created by peripheral-tolerance induction without myeloablative conditioning.

Allogeneic hematopoietic chimerism leading to central tolerance has significant therapeutic potential. Realization of that potential has been impeded by the need for myeloablative conditioning of the host and development of graft-versus-host disease (GVHD). To surmount these impediments, we have adapted a costimulation blockade-based protocol developed for solid organ transplantation for use in stem cell transplantation. The protocol combines donor-specific transfusion (DST) with anti-CD154 mAb. When applied to stem cell transplantation, administration of DST, anti-CD154 mAb, and allogeneic bone marrow leads to hematopoietic chimerism and central tolerance with no myeloablation and no GVHD. Tolerance in this system results from deletion of both peripheral host alloreactive CD8+ T cells and nascent intrathymic alloreactive CD8+ T cells. In the absence of large numbers of host alloreactive CD8+ T cells, the transfusion that precedes transplantation need not be of donor origin, suggesting that both allospecific and non-allospecific mechanisms regulate engraftment. Agents that interfere with peripheral transplantation tolerance impair establishment of chimerism. We conclude that robust allogeneic hematopoietic chimerism and central tolerance can be established in the absence of host myeloablative conditioning using a peripheral transplantation tolerance protocol.

Animals↗
PubMed1994

Cloning and expression of functional cDNA genes of a mouse/human chimeric antibody rcM4.

AIM: The purpose of this study was to clone and express cDNA genes of heavy and light chains of the mouse/human chimeric antibody rcM4, which recognize the sialosyl-Tn epitope of the TAG72 antigen. METHODS: The cDNA genes of chimeric heavy-chain M4H2 and light-chain M4K4 were cloned from the cDNA library of the ccM4 transfectoma. The M4H2 and M4K4 genes were modified in polymerase chain reaction and ligated into mpSV2neo-EP-PA and mpSVgpt-EP-PA to form the heavy- and the light-chain expression vectors mpSV2neo-EP-M4H2-PA and mpSV2gpt-EP-M4K4-PA, respectively. These two expression vectors were then co-transfected into the myeloma cell line SP2/0Ag14. Transfectants were selected in media containing G418 and mycophenolic acid. The rcM4 antibody was purified from transfectant culture supernates by protein A affinity chromatography. RESULTS: The yield of the recombinant chimeric antibody rcM4 from its culture supernates was 6 micrograms/ml. We demonstrated that the rcM4 antibody retained its binding reactivity for sialosyl-Tn and that it was able to mediate effective antibody-dependent cellular cytotoxicity to the human ovarian cancer cell line OVCAR 3 in a manner comparable to the original ccM4 antibody. CONCLUSION: The cDNA genes of chimeric heavy-chains (M4H2) and light-chains (M4K4) could be functionally expressed in the SP2/0Ag14 myeloma cell line. They thus have potential utility in the construction of some novel hybrid proteins such as those containing both antitumor immunoglobulins and cytokine molecules for use in cancer immunotherapy.

Amino Acid Sequence↗
PubMedDate not supplied

Induction of donor-specific transplantation tolerance to skin and cardiac allografts using mixed chimerism in (A + B-->A) in rats.

Mixed allogeneic chimerism (A + B-->A) was induced in rats by reconstitution of lethally irradiated LEW recipients with a mixture of T-cell depleted (TCD) syngeneic and TCD allogeneic ACI bone marrow. Thirty-seven percent of animals repopulated as stable mixed lymphopoietic chimeras, while the remainder had no detectable allogeneic chimerism. When evaluated for evidence of donor-specific transplantation tolerance, only those recipients with detectable allogeneic lymphoid chimerism exhibited acceptance of donor-specific skin and cardiac allografts. Despite transplantation over a major histocompatibility complex (MHC)- and minor-disparate barrier, animals accepted donor-specific ACI skin and primarily vascularized cardiac allografts permanently, while rejecting third party Brown Norway (BN) grafts. The tolerance induced was also donor-specific in vitro as evidenced by specific hyporeactivity to the allogeneic donor lymphoid elements, yet normal reactivity to MHC-disparate third party rat lymphoid cells. This model for mixed chimerism in the rat will be advantageous to investigate specific transplantation tolerance to primarily vascularized solid organ grafts that can be performed with relative ease in the rat, but not in the mouse, and may provide a method to study the potential existence of organ- or tissue-specific alloantigens in primarily vascularized solid organ allografts.

Animals↗
PubMedDate not supplied

Radioimmunotherapy for breast cancer: treatment of a patient with I-131 L6 chimeric monoclonal antibody.

We report the first treatment of metastatic breast cancer by systemic radioimmunotherapy. The serial therapy doses were chosen based on quantitative imaging data in a treatment planning approach. A terminally ill patient with aggressive, locally advanced breast cancer who had failed radiation treatment and chemotherapy was injected intravenously with radiolabeled I-131 chimeric L6, a human-mouse chimeric lgG1 monoclonal antibody to adenocarcinoma. Initially, an imaging 10 mCi dose of I-131 chimeric L6 (dose 1) deposited 8.8% of the injected dose in her chest wall tumor at 48 hours. Ten days later the patient was given a 150 mCi I-131 chimeric L6 dose (dose 2) followed three weeks later by a 100 mCi dose (dose 3). Tumor uptake and retention were comparable for doses 1 and 2, and decreased for dose 3. Following dose 3 the patient developed a manageable thrombocytopenia and transient Grade IV granulocytopenia. The tumor was observed to decrease in size with peak tumor regression occurring two weeks after dose 3. This partial response (PR) was achieved by radioimmunotherapy at a time when conventional therapy had been unable to impact the growth of the patient's massive and aggressive tumor.

Antibodies, Monoclonal↗
PubMed2002

Chimeric IgA antibodies against HLA class II effectively trigger lymphoma cell killing.

Antibodies against human leukocyte antigen (HLA) class II, such as 1D10 or Lym-1, are currently being evaluated for the treatment of B-cell lymphomas. Previous studies have demonstrated that, in addition to IgG Fc receptors, the human myeloid IgA receptor (Fc(alpha)RI, CD89) also effectively triggered tumor cell killing. Therefore, we used the variable light and heavy chain sequences from another murine anti-HLA class II hybridoma, F3.3, to generate a panel of chimeric human/mouse antibodies, including human immunoglobulin A1 (IgA1), IgA2, IgG1, IgG2, IgG3, and IgG4. Antibody production was accomplished by stable transfection of baby hamster kidney cells, and binding activity and specificity were confirmed by enzyme-linked immunosorbent assay (ELISA) and Western blotting. All constructs demonstrated similar binding to HLA class II. Functional studies revealed that chimeric IgG1, IgA1, and IgA2 triggered similar levels of tumor cell lysis. Analyses of effector populations, however, demonstrated that killing by chimeric IgG1 constructs was triggered mainly by human mononuclear cells and complement, while IgA1 and IgA2 mediated effective lysis by polymorphonuclear neutrophils. Importantly, IgG1 and both IgA isotypes were equally effective at killing freshly isolated human chronic lymphocytic leukemia cells. Chimeric IgA antibodies against HLA class II may constitute attractive reagents for lymphoma therapy.

Animals↗
PubMed2004

Modulating erythrocyte chimerism in a mouse model of pyruvate kinase deficiency.

In vivo selection may provide a means to increase the relative number of cells of donor origin in recipients with hemopoietic chimerism. We have tested whether in vivo selection using chemical inducers of dimerization (CIDs) can direct the expansion of transduced normal donor erythrocytes in recipients with chimerism using a mouse model of pyruvate kinase deficiency. Marrow cells from normal CBA/N mice were transduced with a vector (F36Vmpl(GFP)) that promotes cell growth in the presence of CIDs. Transduced cells were then transplanted into minimally conditioned, pyruvate kinase-deficient recipients (CBA-Pk-1(slc)/Pk-1(slc)) to establish stable chimerism. CID administration resulted in expansion of normal donor erythrocytes and improvement of the anemia. The preferential expansion of normal erythrocytes also resulted in a decrease in erythropoietin levels, reducing the drive for production of pyruvate kinase-deficient red blood cells. CID-mediated expansion of genetically modified erythrocytes could prove a useful adjunct to transplantation methods that achieve erythroid chimerism.

Anemia↗
PubMed2005

Chimeric NK-receptor-bearing T cells mediate antitumor immunotherapy.

NKG2D is an activating cell-surface receptor expressed on natural killer (NK) cells and some T-cell subsets. Its ligands are primarily expressed on tumor cells. The aim of this study was to determine whether chimeric NK-receptor-bearing T cells would directly kill tumor cells and lead to induction of host immunity against tumors. Chimeric NK receptors were produced by linking NKG2D or DNAX activating protein of 10 kDa (Dap10) to the cytoplasmic portion of the CD3zeta chain. Our results showed that chimeric (ch) NKG2D-bearing T cells responded to NKG2D-ligand-bearing tumor cells (RMA/Rae-1beta, EG7) but not to wild-type tumor cells (RMA). This response was dependent upon ligand expression on the target cells but not on expression of major histocompatibility complex (MHC) molecules, and the response could be blocked by anti-NKG2D antibodies. These T cells produced large amounts of T-helper 1 (Th1) cytokines and proinflammatory chemokines and killed ligand-expressing tumor cells. Adoptive transfer of chNKG2D-bearing T cells inhibited RMA/Rae-1beta tumor growth in vivo. Moreover, mice that had remained tumor-free were resistant to subsequent challenge with the wild-type RMA tumor cells, suggesting the generation of immunity against other tumor antigens. Taken together, our findings indicate that modification of T cells with chimeric NKG2D receptors represents a promising approach for immunotherapy against cancer.

Animals↗
PubMed2001

Allogeneic chimerism with low-dose irradiation, antigen presensitization, and costimulator blockade in H-2 mismatched mice.

We have previously shown that the keys to high-level nontoxic chimerism in syngeneic models are stem cell toxic, nonmyelotoxic host treatment as provided by 100-cGy whole-body irradiation and relatively high levels of marrow stem cells. This approach was unsuccessful in H-2 mismatched B6.SJL to BALB/c marrow transplants, but with tolerization, stable multilineage chimerism was obtained. Ten million B6.SJL spleen cells were infused intravenously into BALB/c hosts on day -10 and (MR-1) anti-CD40 ligand monoclonal antibody (mAb) injected intraperitoneally at varying levels on days -10, -7, -3, 0, and +3 and the BALB/c mice irradiated (100 cGy) and infused with 40 million B6.SJL/H-2 mismatched marrow cells on day 0. Stable multilineage chimerism at levels between 30% to 40% was achieved in the great majority of mice at 1.6 mg anti-CD40 ligand mAb per injection out to 64 weeks after transplantation, without graft-versus-host disease. The transplanted mice were also tolerant of donor B6.SJL, but not third-party CBA/J skin grafts at 8 to 9 and 39 to 43 weeks after marrow transplantation. These data provide a unique model for obtaining stable partial chimerism in H-2 mismatched mice, which can be applied to various clinical diseases of man such as sickle cell anemia, thalassemia, and autoimmune disorders.

Animals↗
PubMed2001

Integrated src kinase and costimulatory activity enhances signal transduction through single-chain chimeric receptors in T lymphocytes.

Adoptive immunotherapy using receptor-modified T lymphocytes has shown promise in preclinical studies for the treatment of infectious and malignant diseases. These modified T cells express chimeric receptors that link ligand recognition and signal transduction domains in a single gene product. Typically, a single chain Fv fragment is genetically attached to the cytoplasmic domain of the T-cell receptor (TCR) zeta chain. Modulating the signaling characteristics of chimeric receptors will be important for their application to human immunotherapy. It was hypothesized that linking coreceptor and costimulatory signaling motifs together with the zeta signaling domain will enhance receptor function. The present study compares signaling characteristics of 9 single-chain receptors consisting of the H-2K(b) extracellular and transmembrane domains and various combinations of T cell signal transduction domains. Signal transduction regions studied include the TCR zeta chain, the CD4 coreceptor, the lck protein tyrosine kinase, and the CD28 costimulatory receptor. Biochemical characteristics of the receptors, analyzed using calcium flux, receptor, and ZAP-70 phosphorylation, and lck association may be predicted from the known functions of receptor constituents. The combination of zeta together with coreceptor and costimulatory function in a single receptor maximizes chimeric receptor sensitivity and potency. Combining zeta with either the costimulatory or coreceptor function independently also enhances receptor function, though to a lesser extent. It is therefore possible to link TCR, coreceptor, and costimulatory activities in a single functional entity using modular domains. Such receptors demonstrate distinct signaling properties and should prove useful in the development of chimeric receptors for therapeutic purposes.

Amino Acid Sequence↗
PubMed2002

Mixed chimerism induces donor-specific T-cell tolerance across a highly disparate xenogeneic barrier.

Induction of tolerance is likely to be essential for successful xenotransplantation because immune responses across xenogeneic barriers are vigorous. Although mixed hematopoietic chimerism leads to stable donor-specific tolerance in allogeneic and closely related xenogeneic (eg, rat-to-mouse) combinations, the ability of this approach to induce tolerance across a highly disparate xenogeneic barrier has not yet been demonstrated. In this study, we investigated the immune responses of murine T cells that developed in mice with pre-established porcine hematopoietic chimerism. Our results show for the first time that induction of porcine hematopoietic chimerism can eliminate the development of antiporcine donor responses in a highly disparate xenogeneic species. Porcine hematopoietic chimeras showed donor-specific nonresponsiveness in the mixed lymphocyte reaction, lack of antidonor IgG antibody production, and acceptance of donor skin grafts. Thus, mixed chimerism is capable of inducing tolerance in a highly disparate xenogeneic combination and may have clinical potential to prevent xenograft rejection. (Blood. 2002;99:3823-3829)

Animals↗
PubMed2005

Hematopoietic chimerism after allogeneic stem cell transplantation: a comparison of quantitative analysis by automated DNA sizing and fluorescent in situ hybridization.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed mainly in patients with high-risk or advanced hematologic malignancies and congenital or acquired aplastic anemias. In the context of the significant risk of graft failure after allo-HSCT from alternative donors and the risk of relapse in recipients transplanted for malignancy, the precise monitoring of posttransplant hematopoietic chimerism is of utmost interest. Useful molecular methods for chimerism quantification after allogeneic transplantation, aimed at distinguishing precisely between donor's and recipient's cells, are PCR-based analyses of polymorphic DNA markers. Such analyses can be performed regardless of donor's and recipient's sex. Additionally, in patients after sex-mismatched allo-HSCT, fluorescent in situ hybridization (FISH) can be applied. METHODS: We compared different techniques for analysis of posttransplant chimerism, namely FISH and PCR-based molecular methods with automated detection of fluorescent products in an ALFExpress DNA Sequencer (Pharmacia) or ABI 310 Genetic Analyzer (PE). We used Spearman correlation test. RESULTS: We have found high correlation between results obtained from the PCR/ALF Express and PCR/ABI 310 Genetic Analyzer. Lower, but still positive correlations were found between results of FISH technique and results obtained using automated DNA sizing technology. CONCLUSIONS: All the methods applied enable a rapid and accurate detection of post-HSCT chimerism.

Journal Article↗