Pathogenetic studies of cardiac allograft rejection using inbred rat models.
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Animals↗
Biomedical subjects
R D Guttmann
Publications and source records attributed to R D Guttmann.
Isolation of T-lymphocyte lines with specificity for islet cell antigens from spontaneously diabetic (insulin-dependent) rats.
T-lymphocyte lines specific for islet cell antigens were isolated from the spleen and pancreas of newly diabetic BB rats or from the related strain BBUF. These cell lines were grown in continuous culture with interleukin-2 (IL-2) containing medium for greater than 60 days. Such T-lymphocytes responded by proliferation and IL-2 secretion in the combined presence of islet cell antigens and major histocompatibility (MHC)-matched antigen-presenting cells. By fluorescence-activated cell sorter (FACS) analysis the cells were W3/13+, W3/25+, and OX8-. Thus, both functionally and by cell-surface-marker analysis they appear to be of the T-helper phenotype. The long-term growth and study of anti-islet T-lymphocyte lines will permit a detailed analysis of the role of T-lymphocytes in the pathogenesis of IDDM.
Animals↗
Association of anergy and the development of cancer in immunosuppressed renal allograft recipients.
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Blood Transfusion↗
Factors associated with outcome of renal transplantation.
To explore the associations between a number of preoperative risk factors and the failure of renal grafts 99 consecutive patients were followed for up to 7 years after transplantation. The patients had all received their grafts from nonliving donors; the operations were performed at one hospital. Statistical analysis in relation to several outcomes showed that rapidly progressive glomerulonephritis, pre-existing cardiovascular disease, the degree of presensitization to histocompatibility antigens and the donor's being of blood group B were associated with an increased risk of graft rejection or death after transplantation. The risks of acute and accelerated rejection were associated with different factors, which suggests that distinct pathogenetic processes may be involved. The risk of technical failure was associated with immunologic factors, which suggests the possibility that this outcome was not caused by surgical difficulties alone.
ABO Blood-Group System↗
Immunologic dysfunction in patients with classic hemophilia receiving lyophilized factor VIII concentrates and cryoprecipitate.
The occurrence of the acquired immune deficiency syndrome (AIDS) in patients with hemophilia has suggested that an infectious agent transmitted through the frequent use of pooled blood products could be responsible. To determine if the amount or type of factor VIII preparation alters the risk of acquiring immune defects, three groups of asymptomatic heterosexual men were studied: 34 with severe classic hemophilia who were receiving lyophilized factor VIII concentrate, 10 with either mild classic hemophilia or moderately severe von Willebrand's disease who were receiving cryoprecipitate and 22 normal men who served as controls. Anergy was noted in 68%, 57% and 5% respectively of the three groups. In comparison with the control group, the group treated with lyophilized factor VIII concentrate had a significantly decreased mean ratio of helper to suppressor T lymphocytes, poor responses of the lymphocytes to mitogens, high unstimulated background activity of these cells and significantly elevated serum IgG levels. Although some of the patients with classic hemophilia who were treated with cryoprecipitate were also anergic, they did not manifest these in-vitro abnormalities. The data indicate that a majority of apparently immunocompetent individuals with classic hemophilia show in-vivo and in-vitro evidence of impaired cellular immunity and may be at risk for the development of opportunistic infections and neoplasms.
Acquired Immunodeficiency Syndrome↗
Abnormal immunoregulation in patients with insulin dependent diabetes mellitus and their healthy first degree relatives.
Autoantibodies, cell-mediated autoimmunity, and impaired suppressor T cell function, suggesting abnormal immunoregulation, have been implicated in the pathogenesis of juvenile-onset insulin dependent diabetes mellitus (IDDM). To examine one of the parameters of immunoregulation, and to explore its relationship to the disease, we tested suppressor cell function in IDDM patients, their clinically healthy relatives, and in normal unrelated controls. 9/15 IDDM had impaired suppressor cell function compared to 1/8 age-matched healthy sibs (p less than 0.04) and to 0/9 unrelated controls (p less than 0.005). There was no correlation between abnormal suppressor cell function and the patient's age, sex, preprandial blood glucose levels, age at the time of diagnosis, or duration of the disease. However, there was a trend for a higher proportion of HLA Dr3 positive diabetics to have abnormal suppressor cell function compared to DR3 negative patients. Impaired suppressor cell function was also found in 5/23 clinically healthy first degree relatives; 4/5 were related to a diabetic who demonstrated abnormal suppressor cell function. These findings raise the possibility that underlying familial, probably genetically determined abnormalities in immunoregulation, acting in concert with other environmental or genetic factors, may contribute to disease susceptibility in IDDM.
Child↗
Spontaneous diabetes mellitus syndrome in the rat. III. Pancreatic alterations in aglycosuric and untreated diabetic BB Wistar-derived rats.
The pancreatic alterations in aglycosuric and untreated diabetic BB Wistar-derived rats are described. A common finding, often seen in young aglycosuric rats, is that of discrete foci of periductular and/or acinar aggregates of lymphocytes and macrophages. Sites of periductular mononuclear cell infiltrates usually lack endocrine cells. In contrast, foci of acinar infiltrates, although distinct from the predominant endocrine cell mass in the islets of Langerhans, often contain small numbers of alpha and/or beta cells. It is suggested that these clusters of endocrine cells may in some way be antigenically different from those resident in the principal islets and thus serve as an additional target for the immune system in rats bearing the BB genome. The development of overt diabetes requires a massive destruction of beta cells within the islets of Langerhans. Two forms of diabetes mellitus emerge in untreated animals. The more common, designated unstable diabetes, is severe and lethal unless treated with insulin. Less commonly, a stable type of diabetes mellitus ensues for which insulin therapy is not mandatory. In each, the concentration of pancreatic immunoreactive insulin is profoundly decreased, although relatively greater amounts are present in the stable form. Unstable diabetic rats demonstrate a reduction in the concentration of pancreatic immunoreactive glucagon and somatostatin, suggesting that alpha and delta cells also sustain injury in this model of insulin-dependent diabetes mellitus.
Age Factors↗
Spontaneous diabetes mellitus syndrome in the rat. IV. Immunogenetic interactions of MHC and non-MHC components of the syndrome.
We have examined the frequency of three phenotypic characteristics of the syndrome of spontaneous diabetes (overt IDDM, lymphocytic infiltration of the pancreas, and depression of T lymphocytes) in the offspring of crosses between IDDM BB rats and rats of strains with the same and different RT1 genotypes. On the basis of these observations we propose that there are at least three components of the diabetic syndrome in the rat: (1) a requirement for the RT1u haplotype from the BB strain or a gene in close linkage with the gene coding for this haplotype, (2) a susceptibility for development of insular, periductular, or intraacinar lymphocytic infiltration in the pancreas, and (3) a susceptibility to depression of T lymphocytes. Interactions between these components as well as with other genetic and environmental factors contribute to the full expression of the syndrome.
Animals↗
A Class II monoclonal antibody specific for the RT1.B, rather than the RT1.D, product of the rat major histocompatibility complex.
An allospecific monoclonal antibody, 79.7.5., has been shown to be specific for a Class II histocompatibility product of the ACI (RT1.AaBaDa) rat. To further specify the reaction of this antibody to the B or D locus Class II products of RT1, we examined the binding of this antibody to peripheral blood lymphocytes (PBLs) of the WRC rat (haplotype RT1.AnBnDa). Radiolabelled monoclonal antibody 79.7.5. did not bind to PBLs from the WRC rat, but it did bind to PBLs from the WRA rat (RT1.AdBaDa) and the DA (RT1.AaBaDa) rat. These results were confirmed using radiolabelled Staphylococcus protein A in an indirect binding assay. In addition, binding of 79.7.5 could be inhibited by alloantiserum BN anti-BN.1A (DA) (directed against AaBaDa) but not by BN anti WRC (directed against Da). These data demonstrate that monoclonal antibody 79.7.5. reacts with the a allele product of RT1.B rather than RT1.D. This antibody can be used to probe the structures and functional roles of different Class II products of the rat major histocompatibility complex.
Animals↗
The relative roles of MHC and non-MHC genes in heart and skin allograft survival.
Although the role of the major histocompatibility complex (MHC) of the rat (RT1) in graft rejection has been established, the role of non-RT1 genes is not well understood. To investigate the influence of MHC and non-MHC genes in graft rejection, various combinations of congenic and inbred strains of rats were used as donors and recipients of skin grafts and perfused abdominal heart grafts. In addition, hemagglutinating and cytotoxic antibody responses were evaluated to assess loci that were serologically active in transplantation. Our results demonstrate that: (1) RT1 antigens are the most important determinant in heart and skin rejection; (2) antigens controlled by non-MHC genes also play a major role in rejection because they cause disparate heart grafts to be rejected by day 18 and skin grafts by day 26; (3) RT2 cell antigens alone do not cause graft rejection; and (4) allogeneic differences at the RT1, RT2, RT3, and RT6 loci elicit an antibody response in heart transplantation.
Animals↗
Leukocyte subsets in first-set rat cardiac allograft rejection. A serial immunohistologic study using monoclonal antibodies.
For an immunohistochemical analysis of the cells infiltrating rat cardiac allografts undergoing unmodified first-set rejection, functioning Wistar Furth (RT1u) cardiac allografts transplanted to Lewis (RT1(1)) recipients were arbitrarily removed at days 3-6 posttransplantation, and were evaluated histologically using a series of monoclonal antibodies (MAbs) of known cellular distribution, the binding of which was visualized by an indirect immunoperoxidase technique. Sequestered cells present in cryostat sections were segregated numerically on the basis of staining for MAbs detecting T cells, some NK cells, and neutrophils (W3/13); cytotoxic suppressor T cells and most NK cells (MRC OX8); helper T cells and all macrophages (W3/25); B cells and a macrophage subpopulation (MRC OX6, Ia common part determinant); immature T and B cells (MRC OX7, Thy 1.1); and all leukocytes (MRC OX1, LCA). The proportion of cells stained for each MAb was expressed as a percentage of all estimated leukocytes as determined directly on the hematoxylin counterstained sections. Macrophages expressing the W3/25 and MRC OX6 antigens were enumerated on the basis of intracytoplasmic accumulation of previously administered colloidal carbon. There was a significant fall in the relative proportion of W3/25+ carbon- cells within allografts as a function of time. The proportion of mononuclear cells staining for W3/13 and for MRC OX8 showed no statistically significant variation during the period of study. There was a correlation at all periods between the proportional sum of W3/25+ carbon- cells and MRC OX8+ cells and the proportion of W3/13+ mononuclear cells present. The W3/25+ carbon-:MRC OX8+ ratio showed a significant linear decrease with duration of allograft placement. The proportion of carbon+ cells expressing the MRC OX6 and the W3/25 antigens showed a highly significant rise as a function of time. Nonspecific esterase-stained cells showed a similar sequential pattern. These data provide well defined immunohistologic parameters of leukocyte subsets present in unmodified first-set cardiac allograft rejection in the rat.
Animals↗
Spontaneous diabetes mellitus syndrome in the rat. II. T lymphopenia and its association with clinical disease and pancreatic lymphocytic infiltration.
We have studied the occurrence of two phenotypic components (pancreatic lymphocytic infiltration [PLI] of the pancreas and T lymphocytopenia) of the spontaneous insulin-dependent diabetic syndrome (IDDM) in the progeny of hybrids obtained by crossing BB diabetic rats with rats of inbred strains differing from the BB rat at the major histocompatibility complex, RT1. Both PLI and T lymphopenia were seen in animals with all three possible genotypes in both (BUF x BB) and (LEW x BB) lines. PLI was seen in all IDDM animals. T lymphopenia was strongly associated with overt IDDM in both lines (chi 2 = 22.28, p = 0.00002 and chi 2 = 19.28, p less than 0.00001). In addition, T lymphopenia was associated with PLI with and without IDDM in both lines (chi 2 = 8.32, p = 0.0039 an chi 2 = 3.95, p = 0.0467). Not all animals exhibiting PLI without overt IDDM had depressed T cells. Not all animals with T lymphopenia had PLI with or without IDDM. In both lines, the overt IDDM occurred only in animals with at least one RT1 u haplotype derived from the BB rat, confirming our previously reported association of IDDM and RT1. We interpret this evidence to suggest that the overt IDDM syndrome requires one MHC-linked gene and at least two non-MHC-linked genes, which determine susceptibility to PLI and to circulating T lymphocyte depression.
Animals↗
A controlled serial ultrastructural tracer study of first-set cardiac allograft rejection in the rat. Evidence that the microvascular endothelium is the primary target of graft destruction.
In order to define the serial morphologic correlates of unmodified first-set cardiac allograft rejection in an inbred rat strain combination, a series of Wistar-Furth cardiac allografts transplanted to normal nonsensitized Lewis recipients were studied as a function of time with the use of well-documented ultrastructural tracer techniques. Colloidial carbon was employed as a vascular label for detection of microvascular endothelial structural alterations, and horseradish peroxidase was used as a tracer probe for localization of cell-membrane permeability dysfunction of allograft endothelium and cardiocytes as well as of elements of the cellular infiltrate. Wistar-Furth to Wistar-Furth syngeneic heart grafts and Wistar-Furth recipients' own hearts provided appropriate control data. This study was demonstrated that severe diffuse loss of functional and structural integrity of the microvascular endothelium precedes the development of extensive damage to cardiac muscle cells and thus provides strong evidence that the allograft microcirculation is the primary target of immunologic injury. In addition, the sequential pattern of injurious changes present in the rejecting allografts was similar to that observed in certain models of delayed-type hypersensitivity and of skin graft rejection, raising the possibility that lymphokine-mediated mechanisms may be of major pathogenetic significance in this setting.
Animals↗
Genetic analysis of reactivities of allospecific monoclonal antibodies to rat histocompatibility antigens.
The reactions of a number of LEW anti-ACI allospecific rat monoclonal antibodies were examined in a series of breeding studies. Analysis of (LEW X ACI) F2 progeny demonstrated concordance of the monoclonal class I and class II specificities with results of conventional alloantisera typing. In addition, a "gene dosage" effect was noted, with a/a homozygotes showing approximately twice the reactivity as a/l heterozygotes. The previously noted crossreaction of antibody 36.3 (anti-RT1.Aa) with WF and RP strains segregated with RT1.Au in (WF X ACI) F2 and (LEW X RP) F2 progeny suggesting structural similarity of these two allelic products. Finally, an apparent decreased reaction of two (WF X ACI) F2 offspring with antibody 36.3 was shown to be heritable to the F5 generation and may represent an example of genetic control of level of expression of a class I antigen.
Alleles↗
A matched-pair control study of postrenal transplant polycythemia.
Polycythemia developed in 18 of 133 first kidney allograft recipients (13.5%) with onset from the third month to the fifth year posttransplantation. A group of matched nonpolycythemic patients were used as case controls to compare multiple variables in order to identify predisposing factors. In the polycythemia group, there were: (1) significantly more patients who had not undergone pretransplant nephrectomy; (2) significantly more patients who had glomerulonephritis as original disease; (3) significantly more patients who had received pretransplant transfusions; and (4) significantly more patients who were hypertensive posttransplant. Thus, the factors of the presence of native kidneys, original disease, pretransplant transfusions as well as hypertension posttransplant are factors associated with the presence of posttransplant polycythemia. This condition is usually self-limiting and benign.
Adolescent↗
Pain, control over treatment, and compliance in dialysis and transplant patients.
Pain was surveyed via structured interview and the McGill Pain Questionnaire in 53 dialysis and 27 transplant patients. Increased patient control over the dialysis procedure was not associated with a reduction in pain though perceived control may have been. Compliance with the dialysis regimen did not predict pain and the validity of the category "dialysis headache" was questioned. Overall, transplant recipients did not report significantly less pain than dialysis patients. Self-reported depression was correlated positively with pain. The clinical implications of these findings are discussed.
Adult↗
Allospecific monoclonal antibodies recognizing rat class I and class II histocompatibility antigens.
Rat-mouse hybridomas have been developed producing monoclonal antibodies which recognize rat major histocompatibility complex specificities. Splenic lymphocytes from a LEW (RT1l) rat alloimmunized against ACI (Rt1a) splenocytes were used for hybridoma production. The six clones presented demonstrate two patterns of alloreactivity against ACI tissues: clone 36.3 produces an antibody which agglutinates ACI RBCs and binds to ACI splenic lymphocytes and RBCs. Five clones, 65.6, 79.7,1, 79.7.5, 155.3.1, and 189.3.5, from four independent wells produce monoclonal antibodies which bind to ACI splenic lymphocytes but not RBCs. Screening of these six monoclonal antibodies against a reference panel of RBCs and lymphocytes from 15 standard, congenic, and recombinant rat strains indicated that the monoclonal antibody 36.3 detects a RTI.Aa product ( a rat major histocompatibility complex (MHC) Class I antigen) and that 65.6, 79.7.1, 79.7.5, 155.3.1, and 189.3.5 are monoclonal antibodies which recognize a RT1.Ba private specificity (Class II or Ia antigens). These reagents are unique as they are rat monoclonal alloantibodies recognizing private Ia specificities of the rat MHC.
Animals↗
Spontaneous diabetes mellitus in the rat--a powerful probe of MHC and non-MHC immunogenetic interactions.
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Animals↗