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Biomedical subjects

M Jonker

Publications and source records attributed to M Jonker.

At least 91 records · Page 5Linked to original sources
PubMed1989

RFLP analysis of the HLA-, ChLA-, and RhLA-DQ alpha chain gene regions: conservation of restriction sites during evolution.

Genomic DNA samples, derived from a panel of 60 chimpanzees and 45 rhesus monkeys, were digested with the restriction enzymes Taq I and Bgl II and hybridized with an HLA-DQ alpha chain cDNA probe. The results were compared with the data available on a human reference panel. Use of the restriction enzyme Taq I and the DQ alpha chain probe allows the detection of five HLA-DQA1 and two HLA-DQA2 gene-associated fragments within the human population. For the ChLA and RhLA systems, 3 and 7 different DQA1-associated restriction patterns were detected, respectively, while for the chimpanzee a nonpolymorphic DQA2 (DX alpha) gene-associated fragment was also observed. The equivalent of the HLA- and ChLA-DQA2 genes appears to be absent in the rhesus monkey. The ChLA-DQA1 and -DQA2 gene-associated RFLP patterns are identical in man and chimpanzee, whereas such restriction site conservation is not seen in the rhesus monkey. The conclusion drawn is that the genetic organization of the HLA-DQA and ChLA-DQA gene regions, and possibly some of their allelic variabilities, already existed before man and chimpanzee separated in evolution. Moreover, the particular duplication which led to the generation of the HLA- and ChLA-DQA2 genes must have happened before speciation of members belonging to the superfamily Hominoidea (man, chimpanzee, etc), but probably after the separation of superfamily Cercopitecoidea (rhesus monkeys, baboons, etc.) from Hominoidea.

Animals↗
PubMed1989

Shared class II MHC polymorphisms between humans and chimpanzees.

To gain an insight into the evolution of the major histocompatibility complex alleles, three DRB and one DRA genes were isolated from chimpanzee cDNA libraries. The nucleotide sequences of the chimpanzee DRB (ChLA-DRB) genes were then compared with those of the available HLA-DRB alleles by constructing unrooted phylogenetic trees. All three ChLA-DRB genes were found to be more closely related to certain HLA-DRB alleles than unrelated HLA-DRB alleles are to each other. Since available evidence does not support the convergent evolution of MHC alleles, this result is consistent with the idea that closely related ChLA-DRB and HLA-DRB alleles are derived from common ancestral alleles, the existence of which predates the divergence of human and chimpanzee lineages. The predicted amino acid sequences of mature ChLA-DRA and HLA-DRA molecules differ by only one amino acid.

Amino Acid Sequence↗
PubMed1988

Nucleotide sequences of chimpanzee MHC class I alleles: evidence for trans-species mode of evolution.

To obtain an insight into the evolutionary origin of the major histocompatibility complex (MHC) class I polymorphism, a cDNA library was prepared from a heterozygous chimpanzee cell line expressing MHC class I molecules crossreacting with allele-specific HLA-A11 antibodies. The library was screened with human class I locus-specific DNA probes, and clones encoding both alleles at the A and B loci have been identified and sequenced. In addition, the sequences of two HLA-A11 subtypes differing by a single nucleotide substitution have been obtained. The comparison of chimpanzee and human sequences revealed a close similarity (up to 98.5%). The chimpanzee A locus alleles showed greatest similarity to the human HLA-A11/A3 family of alleles, one of them being very close to HLA-A11. Similarly, segments of the ChLA-B alleles displayed greatest similarity to certain HLA-B alleles. The calculated evolutionary branch point for the A11-like alleles is 7 x 10(6) to 9 x 10(6) years, whereas the other A locus alleles diverged between 12 x 10(6) and 17 x 10(6) years ago. Since the human and chimpanzee lineages separated 5 x 10(6) to 7 x 10(6) years ago, our data support the notion that during evolution, MHC alleles are transmitted from one species to the next.

Alleles↗
PubMed1988

Successful treatment of EAE in rhesus monkeys with MHC class II specific monoclonal antibodies.

Experimental Allergic Encephalomyelitis (EAE) was induced in rhesus monkeys by subcutaneous immunization with calfbrain homogenate in complete Freunds adjuvant. Monkeys were treated with major histocompatibility complex (MHC) Class II specific monoclonal antibodies (MoAb) as soon as the first clinical EAE signs became apparent. Two different treatments were tested. One consisted of 10 daily injections of a mixture of two MHC Class II specific MoAb, reactive with a monomorphic structure of rhesus monkey Class II molecules. The other consisted of 10 daily injections of Genox3.53, specific for HLA-DQW1. This MoAb crossreacts well with monkeys and also detects a polymorphism in this species and is presumably reactive with the RhLA-DQW1 antigen. Both MoAb treatments could modify the clinical course of EAE favourably. Untreated animals invariably died within 3 d of the onset of clinical EAE signs. Only one of the three monkeys treated with the monomorphic MHC Class II MoAb preparation died within 3 d, and the other two survived significantly longer than untreated animals. Both animals treated with Genox3.53 survived significantly longer than untreated control animals. Although only a few animals were tested, these results clearly show the possible beneficial influence of MHC Class II specific MoAb on a T-cell mediated autoimmune disease.

Animals↗
PubMed1988

The repopulation capacity of bone marrow grafts following pretreatment with monoclonal antibodies against T lymphocytes in rhesus monkeys.

Complement-mediated lysis of (subsets of) T lymphocytes in bone marrow grafts is increasingly used to prevent acute graft-versus-host disease in human bone marrow transplant recipients, especially in case of major immunogenetic disparity between donor and recipient. Since T lymphocyte depletion has resulted in an increased frequency of allogeneic engraftment failures, its effect on hemopoietic reconstitution was measured in rhesus monkeys. The reactivity patterns of commonly used types of antihuman T lymphocyte monoclonal antibodies (MCAs) with rhesus monkey lymphocytes was analyzed using a double-label cytofluorometry technique and found to be very similar to those with human lymphocytes. The antibodies investigated included CAMPATH-1 (recognizing an antigen present on virtually all lymphocytes and monocytes), OKT4 + 4a (CD4, helper/inducer T lymphocytes), B9 (CD8, suppressor/cytotoxic T lymphocytes), WT-1 (CD7, pan-T), and anti-DR MCAs as stem cell toxic controls. Their possible toxicity to hemopoietic stem cells was studied by using a semiquantitative autologous regeneration assay. Cytotoxic lysis of cells in the bone marrow grafts reacting with the T lymphocyte purging MCAs did not result in delayed regeneration compared to untreated autologous grafts. It is concluded that T lymphocyte depletion using anti-T-lymphocyte MCAs does not influence the repopulating capacity of an autologous bone marrow graft.

Animals↗
PubMed1988

Side effects and immunogenicity of murine lymphocyte-specific monoclonal antibodies in subhuman primates.

The immediate side effects of lymphocyte-specific monoclonal antibody treatment of nearly 150 monkeys is documented in this study. Immediate side effects were only seen with antibodies specific for CD3 and CD8. These side effects are most likely related to stimulation of T cells to produce lymphokines (CD3) and/or to the rapid cell clearance (CD3 and CD8). No immediate effects were observed when CD4 or major histocompatibility complex class II-specific antibodies were injected. These antibodies may therefore be considered for the treatment of graft rejection or autoimmune diseases. Of the 43 animals that received a monoclonal antibody (MoAb) at least 2 years and up to 5 years prior to this study, none has shown any late effects of MoAb treatment. Most animals tested had a vigorous immune response to the injected MoAbs, both antiidiotypic as well as anti-isotypic antibodies were formed. This response was reduced by using Fab2 fragments or by additional immunosuppression, but it was still high enough to prevent further effectiveness of the MoAb treatment.

Animals↗
PubMed1987

The effect of skin allograft survival of a monoclonal antibody specific for a polymorphic CD3-like cell surface molecule in rhesus monkeys.

FN18, a monoclonal antibody specific for the polymorphic rhesus monkey CD3 antigen on peripheral T cells, has been tested for its immunosuppressive effect in a rhesus monkey skin graft model. Animals were injected i.v. daily with antibody and they received an allogeneic skin graft two or three days after the initial antibody treatment. All animals were carefully monitored regarding levels of the major lymphocyte subsets. In animals in which RhT3 (a CD3-like antigen) is demonstrable (i.e. FN18+ phenotype), all T cells initially disappeared from the circulation. However, T cells without RhT3 on their surface reappeared after several days, indicating that these cells must have been modulated. The survival times of the skin grafts were significantly prolonged in these animals. In monkeys in which RhT3 is not demonstrable (i.e. FN18- phenotype), mainly part of the CD4+ lymphocyte subset was depleted. Although less explicit, skin graft survival was significantly prolonged in these animals as well. In both the FN18+ and FN18- groups a difference in sensitivity between the CD4+ and CD8+ cells for the FN18 antibody could be noticed. From the data it appears that FN18 is immunosuppressive and does not have serious side effects. The data are in agreement with information available for the use of OKT3 in clinical immunosuppression. Thus, extrapolation of data from the rhesus monkey model to the clinical situation seems feasible.

Animals↗
PubMed1987

The internal image-like anti-idiotypic response to a CD3-specific monoclonal antibody in primates is dependent on the T cell-binding properties of the injected antibody.

Murine monoclonal antibodies used for therapeutic purposes generally elicit a strong antibody response. A large proportion of this response is specific for the idiotype of the injected monoclonal antibody. The CD3 T cell antigen is polymorphic in rhesus monkeys. A monoclonal antibody, FN18, which detects this polymorphism was used to analyze the immune response to FN18 in FN18+ and FN18- animals. The results of this study show that the internal image-like anti-idiotypic response predominantly occurs in FN18+ animals. This suggests that this type of anti-idiotypic response is limited to cell-binding monoclonal antibodies.

Animals↗
PubMed1987

Idiotype switching of CD4-specific monoclonal antibodies can prolong the therapeutic effectiveness in spite of host anti-mouse IgG antibodies.

Immunotherapy using murine monoclonal antibodies (mAb) is limited by the host anti-mouse IgG response. Previous investigations demonstrated that a large proportion of the anti-mouse response was specific for idiotypic determinants of the mAb. This study demonstrates the feasibility of idiotype switching of therapeutic mAb to evade this anti-idiotype response. In this way prolongation of the therapeutic effectiveness of mAb treatment can be achieved. Using different CD4-specific mAb consecutively in rhesus monkeys it was possible to obtain therapeutic effectiveness in spite of host anti-mouse IgG antibodies, provided that no anti-idiotypic antibodies were present. Anti-constant part antibodies may even enhance therapeutic effectiveness.

Animals↗
PubMed1987

Experimental allergic encephalomyelitis in rhesus monkeys: II. Treatment of EAE with anti-T lymphocyte subset monoclonal antibodies.

Experimental allergic encephalomyelitis was induced in rhesus monkeys by immunization with bovine brain homogenate emulsified in complete Freund's adjuvant. Four monkeys were treated with anti-CD4 (OKT4+4A) monoclonal antibodies after the onset of clinical signs. One monkey developed a chronic-progressive course of EAE and was killed after a significantly prolonged disease of 19 days. One monkey had a relapse and survived with stable neurological signs. Two monkeys fully recovered. OKT4+4A treatment resulted in a short-term clearance of CD4+ lymphocytes and a reduction in granulocytes. Granulocytes may be attracted to the brain by chemotactic factors produced by CD4+ lymphocytes and are responsible for the development of the lethal granulocytic lesions. Clearance of CD4+ lymphocytes successfully prevented granulocytes from migrating to the brain. Nuclear magnetic resonance imaging showed extensive lesions during an acute attack, but these lesions became undetectable when the monkeys recovered. These results indicate that treatment with OKT4+4A can successfully reverse clinical signs of EAE. Four untreated monkeys and one monkey treated with OKT8F died of acute EAE within 3 days of the onset of clinical signs.

Animals↗
PubMed1987

Experimental allergic encephalomyelitis in rhesus monkeys: I. Immunological parameters in EAE resistant and susceptible rhesus monkeys.

Immunological parameters in rhesus monkeys, resistant and susceptible to experimental allergic encephalomyelitis (EAE), were studied. Monkeys immunized with complete Freund's adjuvant (CFA) alone and EAE resistant monkeys immunized with a low dose of bovine brain homogenate emulsified in CFA did not show significant fluctuations in numbers of granulocytes, lymphocytes and lymphocyte subsets (CD4; CD8; GM13, a subset of CD8) and anti-brain homogenate antibody titres remained low. EAE susceptible monkeys immunized with a high dose of myelin developed EAE significantly faster than monkeys immunized with a low dose of brain homogenate. During the induction phase all EAE susceptible monkeys, in contrast to the CFA controls and EAE resistant monkeys, showed an increase in the numbers of granulocytes and the CD4/CD8 ratios and had high antibody titres specific for the immunizing antigens. The most significant disease-related changes were observed after the onset of clinical signs. These included a granulocytosis, a lymphopenia and a decrease in the CD4/CD8 ratio, indicating a selective loss of CD4+ lymphocytes. A major difference between monkeys immunized with myelin and brain homogenate was the significant increase in the percentage of GM13+ lymphocytes after the onset of clinical signs in the latter group. Increases in the CD4/CD8 ratio and antibody titres during the induction phase may be prognostic factors for the subsequent development of EAE.

Animals↗
PubMed1986

Production of primate monoclonal antibodies.

Monoclonal antibodies of primate origin were produced by direct fusion of peripheral blood lymphocytes with two different fusion cell lines: SP2/0, a mouse plasmacytoma line and SBC-H2O, a human-mouse heteromyeloma. The fusion of primate lymphocytes with SP2/0 cells was not successful and only transient production of antibodies was found. The fusion of primate lymphocytes with SBC-H2O cells was more successful and resulted in the establishment of stable monoclonal antibody-producing lines especially when chimpanzee cells were used.

Animals↗
PubMed1986

The human immune response to the OKT3 monoclonal antibody is oligoclonal.

The availability of highly specific and homogeneous antibodies to human T cells by the hybridoma technique has elicited new interest in the clinical use of antibodies to lymphocytes as immunosuppressive agents. OKT3 is the murine monoclonal antibody that has been the most widely used in clinical transplantation to induce immunosuppression. This antibody recognizes a membrane molecular complex, exclusively present on mature human T lymphocytes, which is tightly linked to the T-cell antigen receptor. The long-term therapeutic use of murine monoclonal antibodies in vivo is hampered by the intense antibody response that occurs in most human patients. Thus, when administered alone, OKT3 manifests its immunosuppressive activity only during the 10 to 15 days that precede the onset of sensitization. The results presented here show, by use of isoelectrofocusing, that the antibody response to OKT3, already reported to be restricted in its specificity (only anti-isotypic and anti-idiotypic antibodies are produced), is in addition oligoclonal. This restriction of the anti-monoclonal response may suggest that an efficient way to circumvent the sensitization problem would be to administer consecutively different monoclonal antibodies presenting the same specificity but distinct idiotypes.

Antibodies, Monoclonal↗
PubMed1986

Fine specificity of antibodies produced in rhesus monkeys following in vivo treatment with anti-T cell murine monoclonal antibodies.

The immune response of 23 rhesus monkeys against different murine monoclonal antibodies (mAb) administered in vivo as immunosuppressive agents has been analyzed. Seven mAb specific for either helper-inducer (CD4 molecules) or cytotoxic/suppressor (CD8 molecules) T cells, that cross-react with monkey lymphocytes, were administered i.v. for 10 consecutive days in rhesus monkeys. Nineteen of the animals were recipients of a skin or renal allotransplant. Nineteen out of the 23 monkeys developed a significant immune response against the injected monoclonal. This response was restricted in its specificity since unrelated murine monoclonals were not recognized by the monkeys' anti-monoclonal immunoglobulins. Fine analysis of the monkeys' sera revealed that the antibodies produced against the xenogeneic proteins selectively exhibited two major specificities i.e., anti-isotypic and anti-idiotypic. On a practical basis, these results suggest that an animal already immunized against a given mAb should still be sensitive to the therapeutic effect of another monoclonal sharing the same specificity but different idiotype.

Animals↗
PubMed1986

Differentiation antigens on rhesus monkey lymphocytes. I. Identification of T cells bearing CD3 and CD8, and of a subset of CD8-bearing cells.

Rhesus monkeys provide an excellent preclinical model to test the effect of monoclonal antibodies (mAb) in vitro and in vivo. So far, mostly mAb have been used which were originally raised against human cell surface antigens but cross-reacted reasonably well with homologous antigens on rhesus monkey cells. However, to optimize the model, it was necessary to produce mAb which react specifically with subsets of rhesus monkey lymphocytes. In this report, three mouse anti-rhesus monkey mAb are described, specific for different subsets of rhesus monkey T lymphocytes. None of the reagents cross-reacts with human lymphocytes. Characterization of these mAb was based upon indirect immunofluorescence, using a simultaneous staining technique, and immunoprecipitation of the specific target antigens. One antibody (GM9) reacts with the same subset as is recognized by mAb specific for human CD8+ cells. The second mAb (GM13) is specific for a subset of CD8+ cells. A third mAb (FN18) was of particular interest: it identifies a cell surface complex, RhT3, expressed on mature T lymphocytes, of which the polypeptide chains have a molecular mass of 22 and 27 kDa. The data strongly suggest that RhT3 is a CD3-like determinant, so far unidentified in the rhesus monkey.

Animals↗