The relative contribution of direct and indirect antigen recognition pathways to the alloresponse and graft rejection depends upon the nature of the transplant

In this study, we measured direct and indirect T-cell alloresponses mediated by CD4(+) and CD8(+) T cells in three mouse transplantation models: skin, cornea, and retina. We show that the contribution of direct and indirect antigen recognition pathways to the alloresponse to fully allogeneic grafts varies depending upon the nature of the tissue/organ transplanted. The implications of this finding for understanding the cellular mechanisms by which rejection is mediated in different transplant models are discussed.     

Fat gram target to achieve high energy intake in cystic fibrosis

Higher fat and energy intakes confer a survival advantage in cystic fibrosis (CF). There is a need to develop effective nutrition programmes that ensure optimal energy intake in CF.

Methodology:

A cross-sectional measurement of clinical characteristics and energy and fat intakes in patients attending the CF outpatients clinic of the John Hunter Hospital, Newcastle was undertaken. Twenty-nine subjects, mean age 12 years (range 4.3–20.2), completed weighed food records to determine the contribution of fat to the percentage of the recommended energy intake obtained and to document use of pancreatic enzyme replacement therapy.

Results:

Diets with a high percentage of energy derived from fat did not guarantee that individuals with CF met their energy requirements. Subjects with total fat intakes of 100 g per day or greater, however, achieved in excess of 110% recommended daily intake (RDI) for energy. Up to 47% of subjects consumed more pancreatic enzyme replacement capsules than shown to give maximum effectiveness.

Conclusion:

Setting a 100 g daily fat target is a realistic way of ensuring high energy intakes in CF. Fat ready reckoners would identify the fat content of food and prescribe specific numbers of pancreatic enzyme replacement capsules to be consumed with each meal or food item.     

Antigenicity and immunogenicity of allogeneic retinal transplants

The transplantation of neuronal cells and tissues represents a promising approach for the treatment of incurable neurodegenerative diseases. Indeed, it has been reported recently that retinal transplantation can rescue photoreceptor cells and delay age-related changes in various retinal layers in rodents. However, retinal grafts deteriorate progressively after placement in recipients' eyes. Here we investigated whether a host's immune response elicited toward the graft contributes to its deterioration. Using an ELISA spot assay, we measured T cell responses to retinal tissues placed in the vitreous cavity of syngeneic and allogeneic mice. We found that allogeneic retinas induced potent alloimmune responses mediated by T cells secreting type 1 cytokines (IFN-gamma and IL-2). No response was found in mice engrafted with syngeneic retinas. In addition, all syngeneic retinal grafts displayed no signs of tissue damage (at 55 days), while the majority of allogeneic retinas deteriorated as early as 12 days after placement. Next, we showed that anti-donor responses occurred within two phenotypically and functionally distinct T cell subsets: CD4+ T cells secreting IL-2 and CD8+ T cells producing IFN-gamma. Importantly, CD4+ T cells were necessary and sufficient to cause graft deterioration, while CD8+ T cells did not contribute to this process.     

Donor insemination: child development and family functioning in lesbian mother families

Findings are presented of a comparative study investigating the family relationships and the emotional and gender development of children raised in lesbian mother families. A total of 30 lesbian mother families with 4-8 year old children created as a result of donor insemination (DI) were compared with 38 heterosexual families with a DI child and with 30 heterosexual families who had a naturally conceived child. A variety of assessment measures, including a standardized interview and questionnaires from the parents and psychological testing of the child were used to collect the data. The quality of the couples' relationships and the quality of the mother-child interaction did not differ between lesbian mother families and either of the heterosexual family groups. The quality of the interaction between the social mother and the child in lesbian families was superior to that between the father and the child in both groups of heterosexual families. Childrens' own perception of their parents was similar in all family types; the social mother in lesbian families was regarded by the child to be as much a 'parent' as the father in both types of heterosexual families. With regard to their emotional/behavioural development, boys and girls raised in lesbian mother families were well adjusted and their gender role development did not differ from that of children raised in heterosexual families. These results indicate that child and family development in lesbian mother families is similar to that of heterosexual families.      

Donor insemination: Dutch parents' opinions about confidentiality and donor anonymity and the emotional adjustment of their children

Results from a comparative study investigating 38 donor insemination (DI) Dutch families with 4-8 year old children are presented. The aims of this study were to investigate parents' opinions on the issues of confidentiality and donor anonymity, to assess the emotional development of the children, and to examine in DI families the association between secrecy with regard to the use of a donor and the emotional adjustment of the children. The DI families were compared to families with a child conceived by in-vitro fertilization (IVF) and to families with a naturally conceived child. Secrecy appeared to be associated with DI and not with IVF: 74% of the DI parents intended not to inform the child about the way in which she/he was conceived, whereas none of the IVF parents intended to keep the secret. Only one set of DI parents and two sets of IVF parents had actually told the child. As to donor anonymity, a spread of opinions appeared among DI parents; 57% preferred an anonymous donor, 31% would have liked non- identifying information about the donor, 9% preferred the donor's identity to be registered and 3% remained unsure. Parents' major concern was to know more about the medical/genetic background of the donor. Mothers and fathers in the DI families differed in their opinions concerning the issues of confidentiality and donor anonymity: fathers, more often than mothers, were secretive with regard to the use of a donor and husbands, more often than their wives, were in favour of donor anonymity. With regard to the emotional development of the children, more emotional/behavioural problems were revealed among DI children than among children who were naturally conceived. No association was found between secrecy and the emotional/behavioural adjustment of the children.      

CENTRAL NEUROGENIC NEUROPROTECTION: PROTECTION OF BRAIN FROM FOCAL ISCHEMIA BY CEREBELLAR STIMULATION

Electrical stimulation of the cerebellar fastigial nucleus (FN) elevates regional cerebral blood flow (rCBF) independently of cerebral metabolism (rCGU) throughout brain. One hour of FN stimulation also reduces, by up to 50%, the volume of the focal ischemic infarction produced by occlusion of the middle cerebral artery in rat. Protected areas correspond to the ischemic penumbra. Neuroprotection, while reversible, persists for weeks after 1h of stimulation. It cannot be attributed to increasing rCBF and/or reducing rCGU to improve matching of flow and metabolism. Conditional stimulation of FN initiates long-lived inhibition of expression of peri-infarction depolarizing waves, possibly by altering potassium-channel function and suppresses induction of inducible nitric oxide synthase (iNOS) and ICAM in cerebral microvessels. The brain contains intrinsic networks which may protect the brain from ischemic injury, possibly by producing widespread and longterm suppression of electrical excitability and/or and expression of proinflammatory molecules.     

Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans

Endotoxin is a component of gram-negative bacteria that causes hematologic and immunologic changes through its induction of cytokines. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1 that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity. We investigated the ability of human recombinant IL-1Ra to block the effects of low-dose endotoxin. Fourteen healthy male volunteers between 18 and 30 years old were injected intravenously with 3 ng/kg Escherichia coli endotoxin. Concurrent with the injections, nine volunteers received a 3-hour continuous intravenous infusion of IL-1Ra. The other five subjects were given a 3-hour infusion of saline. Volunteers injected with endotoxin experienced a threefold increase in circulating neutrophils over baseline. This neutrophilia was significantly reduced by 48% in subjects administered endotoxin plus IL-1Ra (P = .0253). Ex vivo mitogen-induced peripheral blood mononuclear cell proliferation decreased by greater than 60% at 3 and 6 hours after endotoxin injection (P = .0053). This endotoxin-induced reduction in mitogen response was reversed in subjects coinjected with IL-1Ra (P = .0253). Endotoxin-induced symptoms, fever, and tachycardia were unaffected by IL-1Ra. IL-1 appears to be an important mediator in endotoxemia because some of its hematologic and immunomodulatory effects can be blocked by IL-1Ra.