Kevin J. Winn

Transplantation tolerance induced by CTLA4-Ig

The rejection of the transplanted allograft is dependent on T cell activation, which requires T cell receptor engagement by antigen and costimulatory signals delivered by T cell surface molecules such as CD28. CTLA4-Ig is a fusion protein that has previously been shown to block the CD28-mediated costimulatory signal and inhibit immune responses in vitro and in vivo. In this report we show that treatment of the C3H/He recipient of a BALB/c vascularized cardiac allograft with a 12-day course of CTLA4-Ig produced indefinite graft survival (> 100 days) in the majority of recipients. In addition, these recipients demonstrated donor-specific transplantation tolerance when tested with donor-specific (BALB/c) and third-party (C57BL/10) skin grafts. These results demonstrate that CTLA4-Ig can induce transplantation tolerance in the adult murine cardiac allograft model.

Prolonged acceptance of concordant and discordant xenografts with combined CD40 and CD28 pathway blockade

BACKGROUND The prompt and vigorous immune response to xenogenic tissue remains a significant barrier to clinical xenotransplantation. Simultaneous blockade of the CD28 and CD40 costimulatory pathways has been shown to dramatically inhibit the immune response to alloantigen. METHODS . In this study, we investigated the ability of simultaneous blockade of the CD28 and CD40 pathways to inhibit the immune response to xenoantigen in the rat-to-mouse and pig-to-mouse models. RESULTS Simultaneous blockade of the CD28 and CD40 pathways produced marked inhibition of the cellular response to xenoantigen in vivo and produced long-term acceptance of xenogeneic cardiac and skin grafts (rat-to-mouse), and markedly suppressed an evoked antibody response to xenoantigen. In addition, this strategy significantly prolonged the survival of pig skin on recipient mice. CONCLUSIONS Long-term hyporesponsiveness to xenoantigen across both a concordant and discordant species barrier, measured by the stringent criterion of skin grafting, can be achieved using a noncytoablative treatment regimen.

CTLA4-Ig plus bone marrow induces long-term allograft survival and donor-specific unresponsiveness in the murine model : Evidence for hematopoietic chimerism

Allograft rejection is dependent on T cell activation, which requires both the engagement of the T cell receptor by antigen in the context of the MHC molecules and costimulatory signals delivered by cell surface molecules such as B7-CD28/CTLA4 pathway. CTLA4-Ig is a fusion protein that blocks this pathway and has previously been shown to prolong both allograft and xenograft survival. The current study demonstrates markedly prolonged murine cardiac allograft survival and specific prolongation of secondary skin grafts using a combination of CTLA4-Ig plus donor bone marrow. A role for hematopoietic chimerism in the establishment of CTLA4-Ig-induced transplantation tolerance was investigated using reverse transcriptase polymerase chain reaction analysis of recipient tissues. Expression of donor-specific MHC class II transcripts in both peripheral and lymphoid tissues was demonstrated at greater than 200 days after transplant. To investigate the functional significance of this observation, heart donors, and donor bone marrow were irradiated before transplantation in CTLA4-Ig-treated recipients. A reduction in allograft survival was associated with irradiation of both the donor heart and the bone marrow. These results suggest that there may be a donor-derived radiosensitive element that enhances allograft survival in this model. Reverse transcriptase polymerase chain reaction analysis of allografts of tolerant and control animals at days 5, 8, and 12 after transplantation failed to demonstrate a dramatic difference in the expression of interleukin (IL)-2, IL-4, IL-10, and interferon-gamma message. Cytotoxicity effector transcripts were largely intact in CTLA4-Ig + bone marrow-treated recipients as they showed no decrease in intragraft granzyme, perforin, Fas, or Fas ligand transcripts during thr first 8 days after transplant. These results imply that complex mechanisms may be important for the induction and maintenance of transplantation tolerance in the CTLA4-Ig plus bone marrow murine cardiac allograft model.

Adjuvant chemotherapy for advanced nasopharyngeal carcinoma in childhood.

Seven children with advanced nasopharyngeal carcinoma younger than 20 years of age diagnosed between 1975 and 1986 (inclusive) were treated with a uniform adjuvant chemotherapy regimen, which consisted of vincristine (1.5 mg/m2; day 1), doxorubicin (45 mg/m2; day 1), 5‐fluorouracil (8 mg/kg; days 1 through 5), and cyclophosphamide (7 mg/kg; days 1 through 5). This combination chemotherapy was given for 12 to 24 months after completion of radiation therapy. The radiation doses to the primary sites ranged from 6000 cGy to a maximum of 6800 cGy. The radiation doses for neck prophylaxis ranged from 4500 cGy to a total of 5000 cGy. Involved sites were irradiated to at least an additional boost of 1000 cGy. One patient had an external dose 6000 cGy to the primary site boosted with brachytherapy of 3000 cGy at the surface of an ovoid. After chemotherapy myelosuppression occurred in all patients and was tolerable. All seven patients are surviving, six disease‐free, for 22 months to 12 years (median, 4 years). This study suggests that the combination of radiation therapy and chemotherapy as used here has acceptable toxicity and is effective and further suggests that children with nasopharyngeal carcinoma, even in its advanced stage at diagnosis, may be curable.

Melanotic neuroectodermal tumor of infancy: MR findings and a review of the literature

Melanotic neuroectodermal tumor of infancy is an uncommon neoplasm occurring primarily in the child one year or less in age [1]. Difficulty in deciding the cellular origin of this tumor has led to numerous names, including congenital melanocarcinoma, melanotic epithelial odontoma, melanotic ameloblastoma, and retinal anlage tumor, to list a few [2]. Electron microscopy and histochemical studies, however, have now established the neural crest as the most likely origin [2]. The most frequent site of occurrence is the maxilla followed by the skull, the brain and the mandible. The genital organs are the most frequent extracranial site [1]. Within the skull, there is a predilection for the anterior fontanel. The following is a case report of a young child with melanotic neuroectodermal tumor of infancy arising at the anterior fontanel. Included is a discussion of magnetic resonance (MR) findings, which to our knowledge, have not been previously reported in this tumor.

Similarities Between Lethal Asphyxia in Postneonatal Rats and the Terminal Episode in Sids

The age-related decrease in asphyxia tolerance was examined in young rats under conditions that mimic prolonged apnea. A precise end point of asphyxia tolerance was determined by calculation of LD50 values for exposed groups. Daily exposure to episodes of sublethal asphyxia did not alter the age-related decrease in asphyxia tolerance. These results permitted further studies in which groups of 10-day-old rats were exposed to 10 min of asphyxia resulting in partial mortality of the group. The postmortem findings in these animals were compared to figures for unexposed littermates. The age-related changes in response to asphyxia and the postmortem findings in asphyxiated animals were compared to the age distribution of sudden infant death syndrome (SIDS) and the postmortem findings in these infants. The comparison showed that the terminal event in SIDS shares many features with lethal asphyxia.

Massive ovarian edema in the pediatric patient: A rare solid tumor

Solid ovarian masses in children are considered malignant unit proven otherwise. The authors report two cases of an unusual, benign, solid ovarian tumor found during ultrasound examination for evaluation of acute abdominal pain. Both patients were found to have a torsed nonviable ovary at the time of laparotomy. Patient 1 was a premenarcheal 10 year old who had undergone a lengthy evaluation for intermittent chronic abdominal pain. The ultrasound examination showed a 9- x 5-cm ovarian mass. Patient 2 was a virilized menarcheal 11 year old with a very large tumor (10 x 7 x 16 cm). The final pathology for both tumors was massive ovarian edema--a rare, stromal, virilizing tumor caused by chronic venous and lymphatic obstruction. Contralateral oophoropexy is a controversial treatment for the remaining ovary. A review of the literature regarding this uncommon tumor is provided.