Invited letter concerning: cytokines and mechanisms of capillary leakage after cardiopulmonary bypass.
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Capillary Permeability↗
Biomedical subjects
J F George
Publications and source records attributed to J F George.
Invited letter concerning: Transplantation tolerance and transplantation.
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Female↗
Developmental regulation of D beta reading frame and junctional diversity in T cell receptor-beta transcripts from human thymus.
During fetal life, both Ig and TCR-gamma delta repertoires are enriched for a specific set of Ag receptors with limited diversity. In order to test the hypothesis that diversification of the human TCR-beta repertoire also follows a developmental program, we examined TCR-beta DJ and VDJ transcripts from fetal and adult thymi. A consistent bias for D beta 1.1 and J beta 1.1 was present in DJ transcripts amplified from 8-wk gestation thymi. Although it is possible to splice and translate D beta 1.1 in all three reading frames, 8-wk gestation fetal DJ transcripts were enriched for D beta 1.1 spliced to J beta 1.1 in reading frame one. Preference for D beta 1.1 reading frame one and for use of J beta 1.1 dwindled with increasing gestational age. Reading frame bias was not affected by the insertion of non-germ-line-encoded nucleotides (N regions) or by the site of gene splicing. In contrast, choice of reading frame and use of J beta 1.1 appeared random in VDJ transcripts from the same 8-wk gestation and adult thymic samples. Among the occasional VDJ transcripts that contained D beta 1.1-J beta 1.1 rearrangements, use of D beta reading frame one was rare. Up to 75% of DJ and VDJ transcripts at 8-wk gestation lacked N regions. Both the percentage of DJ and VDJ transcripts with N regions and the average number of inserted nucleotides per transcript increased with gestational age. Primarily as a result of enhanced N region addition, both the length and sequence diversity of the VDJ junctions increased markedly from 8-wk gestation to adult life with a concomitant increase in the potential size of the TCR-alpha beta repertoire. Terminal deoxynucleotidyl-transferase (TdT), the enzyme associated with N region addition, has not been detected in thymus before 19 wk of gestation. However, we were able to amplify TdT mRNA from all fetal thymi examined. This suggests that TdT may be expressed as early as 8 wk gestation, although at low levels. The early fetal thymus appears enriched for a population of thymocytes that produce minimal quantities of TdT, express a special set of TCR-beta DJ transcripts, and generate a TCR-beta repertoire with limited diversity. These findings support the hypothesis that limitations in the diversity of the TCR repertoire imposed at the time of gene rearrangement contribute to the immaturity of the fetal immune response.
Adult↗
Gamma/delta T cells and alpha/beta T cells differ in their developmental patterns of receptor expression and modulation requirements.
Measurement of the cell surface levels of gamma/delta (TcR 1) and alpha/beta (TcR 2) T cell receptors in the chicken revealed that thymocyte subpopulations that express these receptor isotypes differ remarkably in their rates of receptor acquisition. Whereas TcR 1 expression was relatively high (greater than 10(4) sites per cell) beginning on day 12 of embryonic life, the initial levels of TcR 2 expression on embryonic thymocytes were relatively low (approximately 10(3) sites per cell) when first measurable on day 15, and increased gradually as a function of T cell maturation. In peripheral tissues, the TcR 1 cells also expressed higher receptor levels than did the TcR 2 cells, but the difference was only 2-3-fold. The TcR 2 receptors on immature T cells could be easily modulated by receptor cross-linkage, very much like immunoglobulin receptors on immature B cells. While the TcR 2 receptor modulation occurred within minutes, TcR 1 receptor modulation required several hours for completion, even in the embryonic thymus. The data indicate very different developmental programs for TcR 1 and TcR 2 expression, and suggest fundamental differences in clonal selection modes for the two T cell subpopulations.
Animals↗
HIV-1 and hepatitis B transmission in Sudan.
A seroepidemiologic survey was conducted among 773 male soldiers living in five urban locations in Sudan to study the prevalence of and risk factors for HIV-1 and hepatitis B transmission. Twenty-eight per cent of the study population were born and raised in southern Sudan, an area bordering Kenya, Zaire and Uganda, whilst 72% of the study subjects were from northern Sudan. Seventy-eight per cent of the study population had serologic evidence of past hepatitis B infection, and 13 soldiers were confirmed positive for HIV-1 antibody. All 13 HIV-positive soldiers had recently been deployed in southern Sudan. Multivariate analysis indicated an association between living in southern Sudan and both hepatitis B (odds ratio 8.2) and HIV-1 infection (odds ratio 14). Additionally, sexual relations with prostitutes (odds ratio 1.5) and medical injections for schistosomiasis (odds ratio 2.72) were independent predictors of hepatitis B markers in this military population. The findings of this study suggest that sexual promiscuity is a risk factor for hepatitis B transmission in Sudan. They also indicate one possible route for the spread of HIV-1 from central to northern Africa.
Acquired Immunodeficiency Syndrome↗
Epidemiology of hepatitis B in the Gezira region of Sudan.
To determine the prevalence of and risk factors for hepatitis B infection in rural Sudan, 2 villages in the Gezira were surveyed. There were 851 subjects (age 1-89 years; mean age 24.6 years) of equal sex distribution, 408 from Khalawaat and 443 from Saleim. HBsAg was found in 18.7%, and seropositivity for any hepatitis marker (HBsAg, anti-HBs, or anti-HBc) was found in 63.9%. The prevalence of HBsAg was highest in subjects less than 5 years of age (32.3%). Seropositivity for any hepatitis marker increased from 48.4% in subjects less than 5 years to 88.5% in persons greater than or equal to 50 years of age. HBeAg was present in 70% of HBsAg-positive women of childbearing age. Residence in Khalawaat and parenteral therapy for malaria were found to be independent risk factors for HBsAg-positivity. Age, residence in Khalawaat, crowding, and having had a tattoo were predictive of seropositivity for any hepatitis marker. The reason for increased markers of hepatitis B in Khalawaat compared to Saleim was not apparent.
Adolescent↗
Nasopharyngeal carcinoma not associated with HIV in Sudan.
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Acquired Immunodeficiency Syndrome↗
Primary integumentary allograft reactivity in the American cockroach, Periplaneta americana.
Previous reports have failed to demonstrate integumentary allograft rejection in insects. We realized however, that these studies may not have fully appreciated the structure of the insect exoskeleton. Since the subcuticlar epidermal layer constitutes the only living tissue associated with insect integument, its destruction would indicate that the animal recognized and responded to the foreign tissue. Thus, we investigated allograft reactivity in the American cockroach, Periplaneta americana, by observing the fate of the epidermal portion of the integument. Each animal in a pair received a 3 X 4-mm integumentary allograft from its partner, as well as a 3 X 4-mm control autograft. The transplants were then examined histologically for signs of epidermal destruction at 0, 1, 3, 5, 7, and 10-70 days (in 10-day increments) posttransplantation. The results indicated that significant rejection of the allografts began by day 3, with peak reactivity occurring by day 7 when 92% of the grafts were scored as rejected. At later periods (greater than 20 days), the graft sites showed signs of repopulation by host epidermal cells. The allograft reaction was found to lag behind the xenograft reaction, which showed peak activity after only 1 day posttransplantation. Even so, allograft rejection in this insect occurred quite rapidly (as compared with some other invertebrates), and would appear to be due to a cytotoxic reaction against the epidermal layer.
Animals↗
Alteration of the protein composition in the haemolymph of American cockroaches immunized with soluble proteins.
Previous in vivo experiments demonstrating the existence of humoral immunity in cockroaches prompted us to investigate the composition and number of proteins that are newly induced or increased in quantity in the haemolymph of immune cockroaches compared to saline-injected control animals. SDS-PAGE analysis showed that six different haemolymph proteins of molecular weights 220,000, 162,000, 115,000, 102,000, 95,000 and 45,000 were induced in response to immunization by honeybee toxoid. However, only the 115,000 and 102,000 MW proteins consistently increased in quantity in the haemolymph of females immunized with various other soluble protein antigens, such as phospholipase A2 toxoid and inactivated creatine phosphokinase. Other experiments showed that the 115,000 MW band was not induced in immunized male cockroaches. Therefore, only the 102,000 MW protein was consistently enhanced in all samples of immune haemolymph from animals injected with various antigens. In addition, this protein was found in precipitates recovered from assays where immune haemolymph proteins were precipitated by the antigen. Gel filtration chromatography showed that this induced haemolymph protein is large, and bears an apparent native molecular weight of 600,000 +/- 80,000. This suggests that the 600,000 MW protein may consist of multiple subunits of 102,000.
Animals↗
Recent progress in studies on cell-mediated immune responsiveness in insects.
Comparative immunologists have been engaged in a search for the origins of cell-mediated immunity for a long time. One group of invertebrates that have been receiving increasing attention has been the insects. These animals not only serve as good experimental models, but are of great interest because of their evolutionary success. Several studies have shown that insects generally respond to particular foreign material by mounting an encapsulation reaction. On a more specific level, insects have also been found to be capable of quickly rejecting integumentary xenografts. A basic enigma however, has been the reported inability of insects to respond to integumentary allografts. Recent work from our lab indicates that if one concentrates on the fate of the soft tissue component of the integument, one can readily demonstrate allograft reactivity in these animals. We have now confirmed this by yet another system which monitors the loss of 3H-thymidine from labeled allo- and autografts. Thus, future studies promise to unravel some long sought after questions concerning the evolution of cellular defense mechanisms.
Animals↗
Primary integumentary xenograft reactivity in the American cockroach, Periplaneta americana.
The nature of cell-mediated immunity in the American cockroach (Periplaneta americana) was studied by observing the events involved in graft reactivity. Adult roaches received integumentary xenografts from Blaberus giganteus, as well as control autografts. Grafts were scored histologically by counting the number of nuclei in a 100-mu-wide area under the center of the graft. The data showed that the reaction to the xenografts was characterized by quick recognition of foreignness by day 3 posttransplantation, followed by a slow decline in the cellular response, which lasted for more than 70 days. Control autografts did not appear to stimulate a reaction. Histological examination of xenografts revealed a disruption of the normal cytoarchitecture by a heavy cellular infiltrate. Our findings indicate that the outcome of the response to foreign integument in the roach is more characteristic of an encapsulation reaction than a classic rejection reaction.
Cockroaches↗
Rate of protein synthesis: regulation during first division cycle of sea urchin eggs.
Protein synthesis in fertilized sea urchin eggs, or in 12,000g supernatants derived from them, increased linearly during the period preceding prophase of the first mitotic cycle, dropped during metaphase and anaphase, and increased again after telophase. Similar results were observed for whole cells incubated in the presence of colchicine. These changes in the rate of protein synthesis during the mitotic cycle may be regulated at the translational level.
Amino Acids↗
Methotrexate pulse therapy in the treatment of recurrent acute heart rejection.
Despite cytolytic induction therapy and triple-drug immunosuppression, acute allograft rejection continues to cause important morbidity and occasional death after heart transplantation. Between November 1, 1988, and May 1, 1990, 24 patients received methotrexate pulse therapy for recurrent or persistent acute rejection despite methylprednisolone, OKT3, or antithymocyte globulin therapy. Methotrexate was administered as a daily oral dose of 2.5 to 15 mg on 1 day/week over 3 weeks (longer in 15 patients because of either severe leukopenia with temporary interruption of therapy or recurrent rejection during methotrexate therapy) with reduction or discontinuation of azathioprine. Rejection incidence was reduced from 1.1 episodes/patient month before methotrexate therapy to 0.2 episodes/patient month after completion of therapy (p = 0.0001). Two patients died within 3 months after treatment, one of cytomegalovirus pneumonia and one of lymphoma. Mean white blood count (WBC) fell from 6900 per ml before methotrexate therapy to 3700 during the first month of methotrexate therapy (p = 0.0005). The lowest WBC typically occurred about 3 weeks after starting methotrexate therapy, and a transient WBC of less than 1000/ml developed in seven patients. By multivariable analysis, the WBC 1 month after starting methotrexate therapy was significantly related to greater bone marrow suppression (lower WBC), immediately before methotrexate therapy, greater overall immunosuppression (more rejection episodes) during the 3 months before methotrexate therapy, and a higher total dose of methotrexate. The following conclusions can be drawn: (1) Methotrexate is a useful adjunct in the treatment of recurrent or persistent rejection.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
Total lymphoid irradiation: is there a role in pediatric heart transplantation?
Total lymphoid irradiation (TLI) is an effective adjunct in the therapy of recurrent allograft rejection in adult patients. Between Jan. 3, 1990, and Feb. 5, 1992, TLI was used in 43 heart transplant patients 4 days to 67 months (mean, 6 months) after heart transplantation for recurrent allograft rejection. A mean TLI dose of 700 cGy (range, 40 to 1120 cGy-) was administered during a mean of 7 weeks with adjustment in overall dose and duration determined in part by leukopenia, thrombocytopenia, or both. Among patients who received TLI therapy within 1 month of transplantation (n = 12), the rejection rate decreased from 1.9 episodes per patient per month before TLI to 0.1 episodes per patient per month after TLI (p < 0.001). Sixty percent of patients had no further rejection episodes for 6 months after TLI. Peripheral blood mononuclear cells from two patients were specifically unreactive toward donor stimulator cells in mixed-lymphocyte cultures at 2.5 and 6 months after TLI. During this experience three pediatric patients (ages 10 to 17 years) received TLI at 0.5, 0.8, and 0.9 months after heart transplantation for recurrent allograft rejection. The total TLI dosage for each patient was 720, 800, and 800 cGy. The rejection frequency fell from 1.8 episodes per patient per month before TLI to 0.1 episodes after TLI (p < 0.01). During follow-up of 6 to 25 months after TLI, no adverse sequelae of TLI were identified.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Utility of posttransplantation panel-reactive antibody measurements for the prediction of rejection frequency and survival of heart transplant recipients.
BACKGROUND AND METHODS: Seventy-six heart transplants in 73 patients were studied for the formation of lymphocytotoxic panel-reactive antibodies after transplantation. Treatment of patient serum with dithioerythritol was used to discriminate between antibodies of the immunoglobulin M and immunoglobulin G isotypes. Human leukocyte antigen specificities of immunoglobulin G panel reactive antibodies were determined by the pattern of reactivity with the cell panel used in the panel-reactive antibodies determinations. A total of 465 panel-reactive antibodies determinations were made during the first year after transplantation. RESULTS: Mean panel-reactive antibodies values were highest during the first posttransplantation month. Positive dithioerythritol-treated panel-reactive antibodies values were rare after the first month after transplantation. Multivariable analysis indicated that previous pregnancy and positive cytomegalovirus serologic analysis predicted a higher dithioerythritol-treated panel-reactive antibodies within the first 3 months. No decrease in actuarial survival, increase in cumulative rejection episodes, or increase in the incidence of coronary artery disease at 1 year was seen in patients with a standard panel-reactive antibodies greater than 10% or among patients with dithioerythritol-treated panel-reactive antibodies greater than 0%. A significant and major increase in rejection-related death or retransplantation occurred among 11 patients in whom donor human leukocyte antigen specific antibodies of the immunoglobulin G isotype were detected during the first posttransplantation year (p = 0.02). Two of the 11 patients died of refractory rejection and 3 and 6 months after transplantation, whereas one patient underwent retransplantation for refractory rejection at 13 months and subsequently died. CONCLUSIONS: (1) Posttransplantation serial standard panel-reactive antibodies or dithioerythritol-treated panel-reactive antibodies are not predictive of rejection-related mortality unless the specificity is determined to be antidonor HLA; (2) routine dithioerythritol-treated panel-reactive antibodies studies are advisable during the first month after transplantation, and, if positive (> 10%), antidonor human leukocyte antigen specificity should be determined; (3) detection of recipient immunoglobulin G anti-donor human leukocyte antigen antibodies after heart transplantation identifies a group at high risk for serious allograft rejection and should prompt more intensive rejection surveillance and consideration for additional immunotherapy.
Actuarial Analysis↗