Pretransplant Exposure to Donor HLA-DR Antigen in Random Transfusion Units and the Development of Donor Antigen-Specific Hyporeactivity

Our previous studies have shown that the in vitro assay of donor antigen-specific hyporeactivity is a useful marker for identifying solid organ transplant recipients (kidney, lung and heart) at low risk for immunologic complications (i.e., late acute rejection episodes and chronic rejection). Donor antigen-specific hyporeactivity is defined as a significantly decreased post- vs. pretransplant proliferative response to donor antigens while response to third-party controls remains unchanged. We analyzed whether exposure to the same HLA-DR antigen pretransplant via random blood transfusion and posttransplant via the transplanted organ influenced the development of hyporeactivity. Thirty previously nontransfused recipients, each receiving two 150 ml pretransplant random blood transfusions, were assessed for hyporeactivity at 1 year posttransplant. Of the 12 recipients with pretransplant exposure to kidney HLA-DR via transfusions, 6 (50%) developed hyporesponsiveness; in contrast, of the 18 recipients who were not preexposed, only 3 (15%) exhibited this form of immunomodulation. Of interest, 2 of the 3 hyporesponsive recipients who were not preexposed, received units containing HLA-DR antigens previously shown to share crossreactive epitopes with the kidney HLA-DR. In conclusion, these results suggest a increased incidence in the development of hyporeactivity in patients receiving pretransplant transfusions which share an HLA-DR antigen with the transplanted kidney.     

Renal transplant function after ten years of cyclosporine.

Although the nephrotoxic side effects of cyclosporine are well known, the impact of long-term CsA on renal transplant function is uncertain. We studied 5-10-year renal function in 347 CsA-treated patients, and in 64 randomly selected non-CsA-treated patients who had a minimum of 55 months of graft function. Non-CsA patients had a lower creatinine (Cr) level at one year than CsA patients (P = .001), with no change in renal function over time (P = .6). In CsA-treated patients there was also no suggestion of progressive renal damage, as evidenced by no change in Cr or 1/Cr. Simple linear regression models of 1/Cr vs. time for the first 10 years posttransplant were fit to the data for each patient. Analysis of the Y-intercept estimates from these regressions showed that age (P = .001), sex (P = .001), cyclosporine toxicity (P = .024), and initial cyclosporine dosage (P = .016) significantly affected the one-year serum Cr. Variables not affecting one-year Cr included donor source, early rejection episodes, late rejection episodes, ATN, diabetes, transplant number, HLA ABDR mismatch (for cadaver transplants), maximum PRA, and PRA at transplant. Analysis of the slope estimates from the regressions revealed that only age (P = .001) and late rejection episodes (P = .001) significantly affected the rate of change in 1/Cr over time. We conclude that, in long-term renal transplant patients, there is no evidence of progressive deterioration in renal function due to CsA nephrotoxicity.     

Philosophy, medicine and its technologies.

There is a need to bring ethics and medical practice closer together, despite the risk and problems this may involve. Deontological ethics may promote sanctity of life considerations against the quality of life considerations favoured by consequentialists or utilitarians; while talk of respect for life and the value of life may point to more qualified ethical positions. This paper argues for a respect-for-life position, dismissing a utilitarian cost-benefit outlook as too simplistic; but an unqualified fixed principles approach is also ruled out, both because of its unacceptable consequences in individual cases and also because of its reliance on the slippery slope argument which, it is argued, is logically and psychologically deficient. The case of genetic engineering provides an example in which the notion of respect may operate, but in which broad general principles also apply. A cautious conservatism towards accepted principles is recommended in the development of medical technologies.     

Competitive control of the self-renewing T cell repertoire

We develop a mathematical model for the self-renewing part of the T cell repertoire. Assuming that self-renewing T cells have to be stimulated by immunogenic MHC-peptide complexes presented on the surfaces of antigen-presenting cells, we derive a model of T cell growth in which competition for MHC-peptide complexes limits T cell clone sizes and regulates the total number of self-renewing T cells in the animal. We show that for a sufficient diversity and/or degree of cross-reactivity, the total T cell number hardly depends upon the diversity of the T cell repertoire or the diversity of the set of presented peptides. Conversely, for repertoires of lower diversity and/or cross-reactivity, steady-state total T cell numbers may be limited by the diversity of the T cells. This provides a possible explanation for the limited repertoire expansion in some, but not all, mouse T cell re-constitution experiments. We suggest that the competitive interactions described by our model underlie the normal T cells numbers observed in transgenic mice, germ-free mice and various knockout mice.      

Localization of a gene for otosclerosis to chromosome 15q25-q26

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi- generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease- causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.      

IMPT1, an imprinted gene similar to polyspecific transporter and multi- drug resistance genes

Human chromosome 11p15.5 and distal mouse chromosome 7 include a megabase-scale chromosomal domain with multiple genes subject to parental imprinting. Here we describe mouse and human versions of a novel imprinted gene, IMPT1 , which lies between IPL and p57 KIP2 and which encodes a predicted multi-membrane-spanning protein similar to bacterial and eukaryotic polyspecific metabolite transporter and multi- drug resistance pumps. Mouse Impt1 and human IMPT1 mRNAs are highly expressed in tissues with metabolite transport functions, including liver, kidney, intestine, extra-embryonic membranes and placenta, and there is strongly preferential expression of the maternal allele in various mouse tissues at fetal stages. In post-natal tissues there is persistent expression, but the allelic bias attenuates. An allelic expression bias is also observed in human fetal and post-natal tissues, but there is significant interindividual variation and rare somatic allele switching. The fact that Impt1 is relatively repressed on the paternal allele, together with data from other imprinted genes, allows a statistical conclusion that the primary effect of human chromosome 11p15.5/mouse distal chromosome 7 imprinting is domain-wide relative repression of genes on the paternal homolog. Dosage regulation of the metabolite transporter gene(s) by imprinting might regulate placental and fetal growth.