Contribution of direct and indirect recognition pathways to T cell alloreactivity.

T cells from an HLA-DR11/DR12 responder were stimulated in mixed lymphocyte culture with cells carrying the DR1 antigen. After priming, T cells proliferated in response to both DR1-positive-stimulating cells and a peptide derived from a polymorphic region of the HLA-DR beta 1*0101 chain presented by responder's antigen-presenting cells (APC). The dominant epitope recognized by the primed T cells corresponded to residue 21-42 and was presented by the responder's HLA-DR12 antigen. The DR1 peptide-reactive T cells express T cell receptor V beta 3. The results demonstrate that allopeptides derived from the processing and presentation of donor major histocompatibility complex molecules by host-derived APC trigger alloreactivity. The frequency of T cells engaged in the indirect pathway of allorecognition is about 100-fold lower than that of T cells participating in the direct recognition of native HLA-DR antigen. However, indirect allorecognition may play an important role in chronic allograft rejection, a phenomenon that is mediated by the activation of T helper cells and of alloantibody-producing B cells.

Limited usage of T cell receptor V beta genes by allopeptide-specific T cells.

T cell reactivity to alloantigens results from direct and indirect recognition of allogeneic MHC molecules and/or peptides. Although direct recognition is not self-MHC restricted, indirect recognition, the result of alloantigen processing and presentation by host APC, is restricted by the self (responder) MHC molecule to which the allopeptide has bound. We have studied the MHC restriction and TCR usage in T cell alloreactivity to a synthetic peptide corresponding to amino acid residues 21-42 of the DR beta 1*0101 molecule. T cell lines were developed by in vitro immunization of T cells from three responders carrying the DR beta 1*1101 allele with this peptide. In all three responders, reactivity to peptide 21-42 was restricted by the DR11 molecule. A limited usage of V beta genes was found in these T cell lines, all of which shared the expression of V beta 13.2. Because indirect recognition of allopeptide may play an important role in chronic, antibody-mediated allograft rejection, study of the TCR gene usage may contribute to the development of specific immunosuppression therapy.

T cell recognition of self-human histocompatibility leukocyte antigens (HLA)-DR peptides in context of syngeneic HLA-DR molecules.

It has been suggested that self major histocompatibility complex (MHC) peptides bound to self MHC molecules may be involved in the intrathymic induction of self tolerance. We studied the antigenicity of synthetic peptides derived from the first domain of DR beta 1*0101 chain in a DR beta 1*0101 responder. We found that a peptide corresponding to residues 21-42 of the beta chain could elicit the proliferation of autoreactive T cells. A T cell line (TCL-SUN) and 7 of 9 T cell clones (TCC) derived from TCL-SUN specifically recognized peptide 21-42 in the presence of APCs carrying the DR beta 1*0101 allele. DR beta 1*0101 positive APCs stimulated the TCCs in the absence of peptide, although the magnitude of the response was much lower than in cultures with peptide. This suggests that self DR1 molecules are continuously processed into peptides that are presented by the DR1 molecules on the surface of the cells. The data indicate that some T cells whose TCR binds to self MHC peptides presented by self MHC molecules are not deleted, although their ligand is continuously present. TCCs specific for peptide 21-42 presented in the context of DR1 were also stimulated by cells heterozygous for DR beta 1*0301 and 1601, indicating that some DR peptide-specific autoreactive T cells participate in alloreactivity.

[Histologic and ultrastructural changes in the liver in ageing rats and the effects due to food restriction and noise].

Histologic and ultrastructural changes of the liver in old and non-old Wistar rats and the effects due to persistent restriction of food and exposure to noise were studied. There was increase of hepatocytes with enlarged or double nuclei, and apoptosis as well as fatty change of the liver in the old rats. The incidence of apoptosis and fatty change was lower in those rats with persistent food restriction, but no significant change of the liver was seen in those animals persistently exposed to noisy, environment.

Primary neuroendocrine carcinoma of the liver.

A case of primary neuroendocrine carcinoma in an unusual location, the liver, is reported. The neoplasm was composed of small, uniform cells that had distinct borders and grew in strands, ribbons and nests; its appearance resembled that of a carcinoid. Electron microscopy and special staining of the neoplastic cells confirmed the neuroendocrine nature of the tumor, and the cells showed immunoreactivity for gastrin and pancreatic polypeptide by the PAP. The recent literature is reviewed, and the possible histogenesis of hepatic neuroendocrine carcinoma is discussed.

A correlation between aging and DNA repair in human epidermal cells.

Ultraviolet-induced unscheduled DNA synthesis (i.e. repair synthesis) in human epidermal cells was measured as a function of age. Normal mammary skin specimens were obtained at surgery from 36 female patients, ranging in age from 17 to 77 years. The enzymatically isolated epidermal cells were analyzed for two parameters: (1) the number and percentage of cells carrying out repair synthesis, and (2) the rate of ultraviolet-induced unscheduled thymidine incorporation in individual cells. The results show that the percentage of epidermal cells capable of DNA excision repair synthesis does not decrease significantly with age, but that the rate of unscheduled DNA synthesis in individual cells decreases to a highly significant degree with advancing age.

The effect of age on the number of pituitary cells immunoreactive to growth hormone and prolactin.

The results of a combined immunocytochemical, morphometric, and clinicopathologic analysis of growth-hormone-producing and prolactin-producing pituitary cells in 28 subjects ranging in age from 16 to 90 are reported. There was a significant age-related decline in the number and size of growth-hormone-producing cells, which was most marked in the transition from youth to middle age. There was also a significant age-related decline in the number of pituitary parenchymal cells but not in pituitary weight. Prolactin cells did not show a significant decline in number with age.

Age-related changes in normal human basement membrane.

Basement membranes were studied in the seminiferous tubules of the male, and capillaries of the pectoralis muscles in "normal" males and females. Age-related changes in basement membrane thickness were investigated on electromicrographs by quantitative morphometry. Specimens obtained from either autopsies or surgical procedures were divided into four different age groups ranging from age 16 to age 87 years. The results show a statistically significant increase in the basement membrane thickness correlated with age, in basement membranes associated with both mesenchymal (capillaries) and epithelial (testes) tissue. A comparison of capillary basement membrane in the pectoralis muscle and seminiferous tubule basement membrane in the male show a constant increase in thickness until the age of 60 years, following which only slight increases were noted. The basement membrane thickness in capillaries of the pectoralis muscle in females showed linear increases throughout the lifespan, although at a lower rate than in the male; at age 80 years, it had the same thickness as the male. A comparison of basement membrane thickness between the youngest and oldest groups showed an increase of approximately 50% in all tissues studied.