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R D Guttmann

Publications and source records attributed to R D Guttmann.

At least 19 recordsLinked to original sources
PubMed1992

Identification of natural suppressor cells in long-term renal allograft recipients.

We have previously reported an abnormal expansion of CD3+Leu7+ (CD57+) large granular lymphocytes in long-term renal allograft recipients. These cells lacked NK activity, T-helper activity and did not respond to T cell mitogens. The following studies were done in order to further define the functional characteristics of these cells. We sorted CD3+Leu7+ T cells from the peripheral blood of 45 recipients (all with good renal allograft function), and found that these cells suppress mixed lymphocyte culture responses and pokeweed mitogen-induced IgG secretion in a non-genetically restricted manner. PWM-induced IgG secretion assays are suppressed by 60-100%, and MLC responses are suppressed by 20-85% at a ratio of 1:10 CD3+Leu7+ cells to responder/effector cells. Supernatants from CD3+Leu7+ cell cultures are also suppressive. On the other hand, unsorted cells and non-CD3+Leu7+ sorted cells either enhance responses or produce less than 10% suppression under the same conditions. Patients who were tested more than once showed a relatively stable percentage and suppressive effect of their CD3+Leu7+ cells over an interval of 6-12 months. These nonspecifically suppressive CD3+Leu7+ large granular lymphocytes are similar in many ways to the natural suppressor cells that have been identified in hematopoietic tissues, in graft-vs.-host disease, and in the lymphoid organs of neonates.

Adult↗
PubMed1992

Polygenic nature of spontaneous diabetes in the rat. Permissive MHC haplotype and presence of the lymphopenic trait of the BB rat are not sufficient to produce susceptibility.

We describe the phenotypic characteristics of animals in the fifth backcross-intercross generation of a breeding program in which the RT1 u haplotype and the phenotypic trait responsible for the T-lymphopenia of BB rats have been transferred to the ACI background. In this generation of animals, 24% were lymphopenic with decreased numbers of PBL expressing CD5, TCR alpha, and RT6. The PBL of the lymphopenic animals had a decreased mitogenic response to ConA. All of the nonlymphopenic animals were homozygous for RT6.2. Phenotypic analysis of intestinal IEL revealed that this was also the case for the lymphopenic animals. Moreover, IEL of the lymphopenic animals exhibited a pattern of staining (increased numbers of TCR alpha beta+CD4+CD8+ and decreased numbers of TCR alpha beta+CD4-CD8+) similar to that of BB DP animals. The ACI.1U(BB)-lymphopenic animals, although having two of the genetic traits associated with the expression of spontaneous diabetes mellitus, uniformly fail to develop diabetes. Breeding studies in which these animals were crossed with BB and hBB rats suggest that other genes are necessary for development of overt diabetes.

Animals↗
PubMed1991

Phenotypic expression of bronchoalveolar lavage cells in lung rejection and infection.

The differentiation of episodes of lung allograft rejection from infection continues to be a problem. Bronchoalveolar lavage (BAL) has recently gained some success in the diagnosis and management of interstitial lung disease. To assess the usefulness of BAL in differentiating between lung allograft rejection and infection, we examined the differences in cellular subsets of BAL and peripheral blood (PBL) samples in a controlled canine model of rejection or pneumonia. Single-lung allotransplants were allowed to undergo rejection by withdrawing immunosuppressive agents (n = 6). In another group of dogs (n = 5), pneumonia was induced by transbronchial injection of Pseudomonas aeruginosa and melted agar followed by bronchial fulguration. Cells obtained from bronchoscopic BAL and PBL samples were labeled with functionally characterized cross-reactive murine monoclonal antibodies. Transthoracic needle biopsies and transbronchial biopsies were done to assess their adequacy in examining the rejecting or infected lungs and were compared with open lung biopsies. We found the following: (1) the percentage of DT2-labeled cells was significantly higher (p less than 0.05) in BAL samples from rejecting lungs compared with infected lungs; (2) the PBL/BAL ratio of DT2-labeled cell percentages was significantly higher in pneumonia (1.7 +/- 0.3) than rejection (0.5 +/- 0.2) (p less than 0.004); (3) the percentage of E11-labeled cells in PBL samples was significantly higher (p less than 0.02) in rejection than in infection; and (4) the ratio of WIG4 to DT2 cellular subset percentages in BAL samples from rejection (26.8 +/- 9.9) was significantly lower than from infection (61.0 +/- 22.9) (p less than 0.03). Transthoracic and transbronchial biopsies did not always yield representative specimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Multiple patterns of MHC class II antigen expression on cellular constituents of rat heart grafts. Lack of correlation with graft survival, but strong correlation with vasculitis.

The patterns of induced major histocompatibility antigen expression on indigenous cellular elements of heterotopic rat cardiac grafts were determined by immunohistologic methods in a variety of donor-recipient combinations. Heart grafts were studied in combined full-MHC- and non-MHC-disparate combinations, isolated intra-MHC-disparate combinations, and non-MHC-disparate combinations. The pattern of class II expression on cellular constituents of the grafts was highly variable and critically dependent upon the nature of the specific unidirectional donor-recipient combination. No uniform pattern of class II expression emerged that was clearly predictive of rapidity of rejection or of protracted survival. However, vasculitis was confined to grafts in combinations in which induced class II expression on graft large vessel endothelium was present. Sites of vasculitis were never encountered in the absence of induced class II expression on overlying endothelium. Vasculitis and associated induced class II expression on large vessel endothelium were present in rapidly rejecting grafts and in grafts with indefinite survival. In the latter, vasculitis was shown to progress to a late phase of occlusive intimal thickening. Induced class I expression on graft cardiac myofibers was present in all the genetically disparate donor-recipient combinations examined in this study, irrespective of the length of graft survival. This investigation has shown that no uniform stereotyped pattern of MHC antigen expression on cellular constituents correlates with the length of graft survival. However, induced class II expression on graft large vessel endothelium is closely associated with vasculitis, which can directly progress to occlusive intimal thickening in grafts with prolonged survival.

Animals↗
PubMed1991

Strain-related differences in airway smooth muscle and airway responsiveness in the rat.

The purpose of this study was to evaluate the possible role of the quantity of airway smooth muscle (AWSM) as a determinant of differences in responsiveness between inbred rat strains. To do this, we studied several batches of 8- to 10-wk-old Lewis and Fisher 344 rats. Animals were anesthetized intraperitoneally with pentobarbital (30 mg/kg) and xylazine (7 mg/kg). The peak value of pulmonary resistance (RL) was measured after progressively doubling concentrations of inhaled aerosolized methacholine (MCh). The MCh concentration required to double RL (EC200RL) was calculated as an index of airway responsiveness. Fisher rats were significantly more responsive than Lewis, and the interstrain variability in responsiveness was significantly greater than the intrastrain variability. Additional animals from the less responsive Lewis strain (n = 8) and the more responsive F344 strain (n = 11) were killed immediately after measurement of responsiveness, and AWSM was quantitated as a fraction of total lung tissue using a point-counting technique. F344 rats were again significantly more responsive than Lewis rats (EC200RL geometric mean: 0.72 versus 2.16 mg/ml, p less than 0.005). F344 rats also had significantly more AWSM than did Lewis rats (3.22 +/- 0.176 versus 2.48 +/- 0.185%, mean +/- SE, p less than 0.001). We conclude that highly inbred Fisher rat strains characteristically exhibit a degree of airways responsiveness greater than that of the Lewis strain and that the quantity of AWSM may be an important determinant of interstrain differences.

Airway Resistance↗
PubMed1990

The effects of genetics and age on expression of MHC class II and CD4 antigens on rat cardiac interstitial dendritic cells.

Interstitial dendritic cells (IDC) in normal hearts of inbred rat strains and congenic and congenic recombinant lines were identified and quantitated by immunohistologic methods, on the basis of cellular reactivity with MRC-OX6, a monoclonal antibody (MAb) directed against MHC class II determinants, and with W3/25, a MAb directed against a CD4 epitope. In all strains and lines examined, the W3/25+ IDC frequency was uniformly high with little interstrain variation. In contrast, all rat strains and lines examined showed either high or low OX6+ IDC frequency. Double staining by two color immunofluorescence indicated that strains with a low OX6+ IDC frequency were characterized by a high frequency of W3/25+ OX6- IDC and a low frequency of W3/25+ OX6+ IDC. In strains with high OX6+ IDC frequency, the majority of IDC coexpressed both markers. Comparative analysis of (i) MHC identical background disparate strains and lines, (ii) MHC disparate background identical strains and lines, and (iii) F2 segregation analysis of intercrosses and backcrosses derived from an original cross between high and low frequency OX6+ IDC strains, all indicated that OX6+ IDC frequency is dependent upon both MHC- and non-MHC-linked genetic factors. It is suggested that rat cardiac OX6+ IDC frequency is influenced by a minimum of two autosomal genes, one of which is MHC linked. The frequencies of both W3/25+ IDC frequency reached adult levels by 10 days of age; adult levels of OX6+ IDC were not attained until Day 21. It is postulated that in the rat heart, W3/25+ OX6- IDC are potential precursors of W3/25+ OX6+ IDC, and that the cellular frequency of coexpression in the adult is under genetic influence. Whether these genetic factors modify constitutive or physiologic levels of class II-inducing lymphokine activity, or influence cellular susceptibility of IDC to induced class II expression is unclear.

Age Factors↗
PubMed1990

A single dose of the MHC-linked susceptibility determinant associated with the RT1u haplotype is permissive for insulin-dependent diabetes mellitus in the BB rat.

Syndromes of insulin-dependent diabetes mellitus (IDDM) have been described in the mouse, in the rat and in man. In all three species, the presence of one or more specific alleles of the major histocompatibility complex is a prerequisite for the appearance of the disease. In the BB rat, diabetes is associated with the RT1u haplotype. We have performed a series of intercrosses of diabetic BB rats with normal Lewis and Buffalo rats and examined the offspring of all litters producing at least one diabetic animal. Forty-five of the 250 rats that developed diabetes were heterozygous for the RT1u haplotype by serotyping. Furthermore, the diabetic rats heterozygous by serotyping at the RT1A class I loci were also heterozygous at the RT1B and RT1D loci of the class II region and did not show evidence of a recombinant haplotype when examined by Southern blot analyses using molecular probes for class I and class II genes. Diabetic rats heterozygous or homozygous for RT1u were phenotypically indistinguishable with respect to age of onset and severity of disease. Therefore, in the rat, as in the human, a single dose of the high-risk allele at the major histocompatibility complex is sufficient for the development of IDDM if other susceptibility factors and the appropriate environmental factors are in place.

Animals↗
PubMed1989

CD4+/Leu-7+ large granular lymphocytes in long-term renal allograft recipients. A subset of atypical T cells.

In long-term renal allograft recipients on conventional immunosuppression, we have previously reported an abnormal expansion of CD3+/Leu-7+ cells. These cells are large granular lymphocytes without any natural killer activity. About 20% of these CD3+/Leu-7+ cells coexpress the CD4 differentiation antigen. In 65 transplant recipients at risk for more than 6 months, the mean percentage of peripheral blood CD4+/Leu-7+ cells is significantly increased compared with 34 normals (5.0 +/- 0.6% versus 1.0 +/- 0.1%, P less than 0.0001). Patients who never received azathioprine do not show such an abnormality. We carried out this study to further define the phenotype, morphology, and function of these cells. As to phenotype, they coexpress CD2, CD3 but do not coexpress CD1, CD8, CD11, CD16, CD19, CD25, HLA-DR, Leu-M3. Morphologically, CD4+/Leu-7+ cells are typical large granular lymphocytes undistinguishable from CD16+ effector NK cells. CD4+/Leu-7+ cells do not exhibit any natural killer cell activity. In contrast to CD4+/Leu-7- cells, CD4+/Leu-7+ cells do not proliferate when stimulated with either lectins (Con A, PHA) or allogeneic cells. When stimulated for 3 days with PHA, sorted CD4+/Leu-7+ cells do not express IL-2 receptors as detected with a PE-conjugated anti-CD25 monoclonal antibody, whereas 40% of CD4+-Leu-7- cells do so. Finally, when stimulated with PHA, CD4+-Leu-7+ cells are not able to produce detectable levels of IL-2, while CD4+-Leu-7- cells do so. In long-term renal allograft recipients on conventional immunosuppression, Leu-7 antigen identifies a subset of CD4+ cells that do not behave like regular T helper cells. We speculate that these cells represent an alteration in the cellular environment in transplant recipients, perhaps leading to long-term complications such as cancers and chronic viral infections.

Adult↗
PubMed1989

Interferon-gamma induces transcription and differential expression of MHC genes in rat insulinoma cell line RINm5F.

We have reported that enhanced levels of class I major histocompatibility complex (MHC) antigen are expressed throughout the islets of prediabetic and newly diabetic BB rats and that the endocrine cells of the islet remained class II negative. In this study we investigated the molecular biology of lymphokine-induced expression of the class I and II MHC genes in subclones of the rat insulinoma cell line RINm5F. Treatment of a particular subclone of RINm5F cells (which are normally class II negative, class I low expressors) with crude lymphokine preparation or various doses of recombinant interferon-gamma resulted in enhancement of MHC class I antigen expression but no detectable induction of class II antigen expression. This enhancement of class I antigen expression was a dose-dependent phenomenon and was preceded by a dose-dependent increase in class I-specific RNA. Both class I and II genes were induced at the transcriptional level, as determined by Northern blotting and in vitro nuclear transcription assays, but exhibited strikingly different induction kinetics. Supernatants from concanavalin A-stimulated splenocytes had a similar class I-restricted inductive effect on MHC gene expression. This subclone of RINm5F cells, which exhibits a class I lymphokine response-positive, class II response-negative phenotype, 1) mimics the behavior of beta-cells in the prediabetic and newly diabetic pancreas and 2) represents a valuable system for probing the similarities and differences in the lymphokine-mediated induction pathways for class I and II MHC genes.

Adenoma, Islet Cell↗
PubMed1989

Absence of collagen deficiency in familial cerebral aneurysms.

It has been suggested that a deficiency in the expression of type III collagen may play a role in the pathogenesis of cerebral aneurysms. To test this hypothesis in cases of familial cerebral aneurysms, fibroblast cell cultures were established and the expression of collagen types I and III was studied in a patient with three cerebral aneurysms whose mother and sister also had cerebral aneurysms. Cultured skin fibroblasts were labeled with tritiated proline. The collagens and procollagens were precipitated and run on sodium dodecyl sulfate-polyacrylamide gel electrophoresis after reduction to analyze procollagen chains. Control cell lines were analyzed simultaneously. Quantitation of the ratios of type III to type I procollagen synthesis was achieved by integration of the intensities of the pro-alpha 1(III), pro-alpha 1(I), and pro-alpha 2(I) bands on fluorograms of electrophoretic gels of medium proteins. There was no difference in type I and III procollagen levels observed between the cells from the aneurysm patient and those from the control cell lines. These data do not support the hypothesis that familial cerebral aneurysms are caused by a deficiency of type III collagen.

Collagen↗