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Biomedical subjects

M J Holterman

Publications and source records attributed to M J Holterman.

13 recordsLinked to original sources
PubMed2003

Living-related bowel transplantation to treat short bowel syndrome in a four-year-old child: a case report.

PURPOSE: Short bowel syndrome (SBS) is an extremely challenging clinical problem in children. Although many patients can be maintained for a period of time on total parenteral nutrition (TPN), many of these children suffer from the morbidity and mortality associated with sequential central line infections, venous thromboses, and TPN-induced liver failure. Intestinal transplantation often is the only chance for long-term survival. Unfortunately, many children die every year waiting for size-matched cadaveric intestine to become available. METHODS: After our success with living-related bowel transplantation in adults, the authors successfully transplanted 150 cm of maternal ileum into a 4-year-old 10-kg child with profound malnutrition from SBS and advanced TPN-induced liver failure. Because of the size mismatch, the abdominal cavity could not be closed primarily. The defect was covered with absorbable mesh and subsequently with skin graft. RESULTS: The patient is home with excellent bowel and liver function, off hyperalimentation, and on a regular diet. No rejection has been encountered. CONCLUSIONS: Living-related intestinal transplantation is a life-saving alternative to cadaveric intestinal transplantation in children with short bowel syndrome.

Child, Preschool↗
PubMed2001

Targeted delivery of anti-CTLA-4 antibody downregulates T cell function in vitro and in vivo.

CTLA-4 is a T cell surface molecule that binds to the costimulatory molecules CD80 and CD86 on antigen-presenting cells and downregulates T cell function. Therefore, we wanted to test whether antigen-specific activated T cells could be inhibited through directed CTLA-4 signaling using a bispecific antibody (BiAb) capable of simultaneously binding to CTLA-4 and a tissue-specific antigen. The BiAb was prepared by linking two separate monoclonal antibodies against CTLA-4 and the thyroid-stimulating hormone receptor (TSHR). The mouse B cell lymphoma line M12 (H2(d)) was used to induce alloreactive T cells in CBA/J mice (H2(k)); M12 cells stably transfected with the cDNA encoding murine TSHR (mM12) were used to restimulate the alloresponse in vitro. Results of assays for in vitro T cell proliferation, IL-2 production, and cytotoxicity in the presence of BiAb demonstrated that the BiAb could inhibit the T cell alloresponse when stimulated with mM12 cells but not with M12 cells. This effect was dependent on binding of TSHR-bound BiAb to CTLA-4, since the addition of soluble CTLA-4-Ig blocked the inhibitory effect. Injection of mM12 cells, along with the BiAb, not with antibodies against TSHR or CTLA-4 either separately or together, into CBA/J mice (H2(k)) downregulated alloreactive T cell responses. Our study demonstrated that the presence of CTLA-4 signaling molecules on the surface of target cells can protect those cells from immune attack by antigen-specific T cells and suggested that a similar approach could have potential therapeutic value in transplant rejection and tissue-specific autoimmune diseases.

Abatacept↗
PubMed2001

Paraneoplastic pemphigus and bronchiolitis obliterans associated with a mediastinal mass: A rare case of Castleman's disease with respiratory failure requiring lung transplantation.

Castleman's disease is an infrequent and usually benign lymphoproliferative disorder. Resection of the tumor usually is curative. The immunostimulatory nature of the tumor can, in rare instances, result in paraneoplastic manifestations. The authors present a case of a 14 year old with mucocutaneous ulcerations and progressive dyspnea that was found to have a large mediastinal mass and circulating autoantibodies that were responsible for his paraneoplastic pemphigus and bronchiolitis obliterans. In spite of aggressive immunotherapy to control the autoimmune mucocutaneous lesions, the pulmonary fibrosis was irreversible and progressed to pulmonary failure necessitating lung transplantation. J Pediatr Surg 36:E22.

Adolescent↗
PubMed1999

Combinatorial search of substituted beta-cyclodextrins for phosphatase-like activity.

Thirteen per-6-akylamino-6-deoxy-beta-cyclodextrin libraries (beta-CD libraries) were generated by a solution-phase combinatorial synthesis starting from per-6-iodo-6-deoxy-beta-CD and different combinations of eleven individual amine nucleophiles. Certain libraries showed the ability to hydrolyzep-nitrophenyl phosphate in the presence of Zn2+.

Combinatorial Chemistry Techniques↗
PubMed1996

Surgical implications of necrotizing fasciitis in children with chickenpox.

Varicella (chickenpox) affects approximately 90,000 children each year. Although most cases resolve, some develop necrotizing soft tissue infections secondary to group A streptococcus and staphylococcus. Delay in diagnosis is common. At the time of initial presentation, the need for surgical intervention is not always clear. The authors conducted a retrospective review of 30 patients with varicella (seen from December 1993 to June 1995) for whom there was clinical concern for necrotizing soft tissue infection. Various parameters were examined, including tachycardia, band count, temperature, and clinical symptoms, to differentiate the children who required surgery from those who did not. Of the 30, 22 underwent surgery. Eighteen had necrotizing fasciitis and required debridement, and four had abscesses that were incised and drained. Eight patients had simple cellulitis and did not require operation. Group A streptococcus was the most common organism cultured. All patients were treated with appropriate antibiotics. Twenty of the 22 surgical patients had elevated band count (> or = 5%), 21 had tachycardia, and 18 were febrile at the time of presentation (> 4 days after the onset of chickenpox). Although all patients with necrotizing fasciitis had tachycardia, this sign was a less specific indicator for surgery than was increased band count. Severe pain, erythemia, and induration was the most common signs/symptoms in the surgical patients. The survival rate for these 30 patients was 100%, and there was little long-term morbidity. The authors recommend immediate surgical intervention for children with chickenpox who present more than 2 or 3 days after the onset of the viral illness with symptoms that include fever, tachycardia, and an elevated band count in association with an erythematous, indurated, painful lesion. With this sign/symptom complex, the presumptive diagnosis must be necrotizing fasciitis until proven otherwise. If the patient has suspicious symptoms or if these symptoms are associated with tachycardia or an elevated band count, the patient warrants admission, institution of intravenous fluids, nafcillin, clindamycin, and close observation over several hours. If the symptoms progress over the next few hours or if the tachycardia persists despite rehydration and antibiotics, the patient should be taken to the operating room for exploration. The authors strongly endorse such exploration despite the risk of a negative operation, because the morbidity and mortality associated with delayed surgical treatment are potentially significant. With prompt aggressive surgical and medical treatment, a good outcome can be anticipated for these patients.

Anti-Bacterial Agents↗
PubMed1989

Cytotoxic T cell responses in HLA-A2.1 transgenic mice. Recognition of HLA alloantigens and utilization of HLA-A2.1 as a restriction element.

Previous studies have indicated that the frequency of murine CTL precursors (CTLp) for human class I molecules is one to two orders of magnitude lower than that for murine class I alloantigens, and that this is due to species-specific structural differences between these molecules. Transgenic mice expressing the human class I MHC Ag HLA-A2.1 were used to examine changes in the frequency of class I HLA-specific precursors after T cell differentiation in an HLA-A2.1 positive environment. The HLA-A2.1 gene product was expressed at levels comparable to those of the endogenous H-2Db molecule in thymus, bone marrow, and spleen. By limiting dilution analysis, it was observed that the frequencies of CTLp in transgenic mice responding to the human alloantigens HLA-B7 or HLA-A2.2 were comparable to or lower than those in normal C57BL/6 mice, regardless of whether the Ag was presented on human or murine cells. Thus, expression of a human class I molecule in these animals did not result in an expansion of the number of CTLp specific for other human class I Ag. In addition, the frequency of HLA-A2.1-restricted, influenza specific CTLp was substantially lower than the frequency of H-2b restricted CTLp, indicating a poor utilization of HLA-A2.1 as a restricting element. Finally, the frequencies of CTLp for HLA-A2.1 expressed on syngeneic murine tumor cells were decreased significantly. Thus, expression of HLA-A2.1 in these animals appeared to induced tolerance to this Ag. Interestingly, however, these mice were not tolerant to the HLA-A2.1 molecule expressed on human cells. This indicates that the HLA-A2.1 associated epitopes expressed on murine and human cells differ and suggests that, under these circumstances, HLA-A2.1 acts as a restricting element for human nominal Ag. These results are discussed in the context of current models of T cell repertoire development.

Animals↗
PubMed1988

Species-specific structural differences in the alpha 1 + alpha 2 domains determine the frequency of murine cytotoxic T cell precursors stimulated by human and murine class I molecules.

The frequency of murine CTL precursors (CTLp) that recognize the human histocompatibility Ag HLA-A2 and HLA-B7 was measured and found to be approximately two orders of magnitude lower than the frequency of CTLp that recognize murine H-2 alloantigens. The possible contribution of other cell surface molecules to this difference in response was addressed by expression of the H-2Ld molecule on a human cell and the HLA-B7 molecule on a murine cell. It was found that both human and murine H-2Ld expressing cells elicited comparable levels of H-2Ld specific CTL. Although murine HLA-B7 positive cells stimulated a higher frequency of HLA-B7-specific CTLp than did human cells, this appeared to be largely due to stimulation of CTLp that recognized HLA-B7 in the context of H-2 molecules; consequently, it was concluded that the difference in the frequency of murine CTLp elicited by human and murine class I Ag is due to species specific structural differences in these molecules. The regions of the class I molecule that were responsible for this difference were mapped using chimeric class I molecules constructed to replace domains of the human molecule with their murine counterparts. It was found that the frequency of CTLp is controlled by structures within the alpha 1 and alpha 2 domains of the molecule. These results are discussed in the light of models for T cell recognition of class I Ag and the diversification of the T cell receptor repertoire.

Animals↗
PubMed1987

The ability of cytotoxic T cells to recognize HLA-A2.1 or HLA-B7 antigens expressed on murine cells correlates with their epitope specificity.

Two groups of human and murine cytotoxic T lymphocyte (CTL) clones specific for human leukocyte antigen (HLA)-A2 or -B7 can be distinguished based on their ability to kill murine transfectants expressing these molecules. The clones which do not recognize murine transfectants exhibited greatly reduced conjugate formation with these cells, indicating that the inability to lyse these cells occurs in recognition and binding. No systematic differences in inhibitory titer between the two types of CTL clones were seen with anti-CD8 (Lyt-2), anti-LFA-1, or monoclonal antibodies against HLA class I molecules. However, blocking with anti-HLA class I monoclonal antibodies suggested that different CTL clones recognized spatially separate epitopes on HLA-A2 and -B7. In addition, a correlation between the inability to recognize murine transfectants and fine specificity was seen. Eight of nine clones which did not lyse murine transfectants also failed to recognize human cells expressing HLA-A2.2 or -A2.3. In contrast only 5 of 12 clones which lysed transfectants failed to recognize the variant molecules. Analogous data were obtained with human CTL clones raised against HLA-A2.1. These findings suggest that CTL clones that do not lyse murine cells expressing appropriate antigens recognize epitopes that have been altered or lost as a consequence of expression on the murine cell surface. It is suggested that the loss of HLA-associated epitopes on the murine cell surface may be due to differences between mouse and human cells in the processing or presentation of class I-associated peptides.

Animals↗
PubMed1986

HLA antigens expressed on murine cells are preferentially recognized by murine cytotoxic T cells in the context of the H-2 major histocompatibility complex.

The frequency of murine cytotoxic T lymphocytes (CTL) capable of responding to HLA antigens expressed on human or murine cells was determined by limiting dilution analysis. HLA antigens expressed on human cells stimulated CTL with a precursor frequency of about 1 in 2 X 10(5) spleen cells in primed mice, over two orders of magnitude weaker than a primary allogeneic response. There was a 10-fold increase in the frequency of precursors responding to HLA antigens when they were expressed on murine cells. It was determined that the increased frequency of responders was due to CTL that could only recognize HLA antigens on the syngeneic murine line to which they had been stimulated and that these CTL could not lyse any other HLA expressing murine cells of different H-2 haplotypes. The lytic activity of these CTL was inhibited by H-2b-specific antibodies. These results indicate that such CTL recognize HLA antigens in the context of the H-2 major histocompatibility complex. The magnitude and specificity of CTL responses to xenoantigens are discussed in the context of a model for T-cell interactions with major histocompatibility antigens.

Animals↗
PubMed1985

Construction of novel class I histocompatibility antigens by interspecies exon shuffling.

Human and mouse class I histocompatibility antigens share considerable structural homology at both the protein and DNA sequence level. This homology has allowed the production of hybrid class I molecules by the reciprocal exchange of DNA sequences corresponding to equivalent domains of HLA-B7 and either H-2Ld or H-2Dd. It is shown that these genes give rise to protein products that are stably expressed on the surface of murine L cells after DNA-mediated gene transfer. These proteins express only those monoclonal antibody-defined H-2 determinants that are expected based on their genetic construction. The molecules have allowed the localization of a number of polymorphic and monomorphic HLA-specific epitopes. In all but one case, expression of an epitope on a domain does not appear to be influenced by the replacement of adjacent human domains with their murine equivalents, suggesting a considerable degree of structural independence of the domains. Cells expressing the hybrid molecules have also been tested as targets for a panel of HLA-B7-specific cytotoxic T cell clones. The results show that the polymorphic determinants recognized by these clones map to the alpha 1 and alpha 2 domains of the HLA-B7 molecule. No evidence for an influence of species-related amino acid sequence differences in the third extracellular domain on T cell recognition was seen. The results are discussed in light of the proposed domain structure of the class I proteins and the potential use of such molecules for further functional studies.

Animals↗
PubMed1984

Cytotoxic T lymphocyte recognition of HLA-A/B antigens introduced into EL4 cells by cell-liposome fusion.

HLA-A2 and -B7 antigens were introduced into EL4 (H-2b) cells by cell-liposome fusion and were used as targets or stimulators for cytotoxic T lymphocytes (CTL) generated in C57B1/6 (H-2b) mice. It was found that such EL4-HLA cells were not recognized by CTL that had been raised against either a human cell line bearing these HLA antigens or the purified HLA-A2 and -B7 antigens reconstituted into liposomes. In addition, EL4-HLA cells were not capable of inducing CTL that could recognize a human cell line bearing HLA-A2 and -B7 antigens. Instead, EL4-HLA cells induced CTL that specifically lysed EL4-HLA cells and not human cells expressing HLA-A2 and -B7. CTL recognition required the presence of HLA antigens on the EL4 cell surface and was inhibited by antibodies against either H-2b or HLA-A/B. Monoclonal antibody binding studies showed that the expected polymorphic determinants of the HLA-A2 and -B7 antigens were still present on EL4-HLA cells. However, the specificity of CTL or their precursors that are capable of recognizing HLA-A2 or -B7 was altered after these antigens became associated with the EL4 surface. Possible explanations for these results are discussed.

Animals↗
PubMedDate not supplied

Cardiovascular embryology.

During the first 20 days of development, the human embryo has no cardiovascular structure. Over the next month, the heart and great vessels complete their development and look very much like they will at full gestation. This amazing process transforms isolated angiogenic cell islets into a complex, four-chambered structure. During this transformation, the single heart tube begins to beat at 23 days of development and by 30 days blood circulates through the embryo.

Cardiovascular System↗