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R M Ferguson

Publications and source records attributed to R M Ferguson.

At least 145 records · Page 8Linked to original sources
PubMed1987

Sequential antilymphoblast globulin and cyclosporine for renal transplantation.

The nephrotoxic effects of cyclosporine (CsA) seem to be augmented by co-existing renal injury. A high rate of prolonged delayed function (acute tubular necrosis [ATN]) and non-function (NF) has been associated with the use of CsA prior to and following renal transplantation. Cyclosporine has also been associated with a slower recovery of allograft function and poor baseline renal function even in allografts that function immediately compared with conventionally treated recipients. In 1983 we hypothesized that the rate of ATN and NF following renal transplantation could be decreased and more normal kidney function achieved if renal injury was resolved before adding the nephrotoxic effects of CsA. A group of 300 nonsplenectomized, uremic recipients have received 304 renal transplants and have been initially immunosuppressed with azathioprine, prednisone, and Minnesota antilymphoblast globulin (ALG) prior to starting maintenance CsA and prednisone. The incidence of NF has been 1.9% and the development of ATN has been 7.6% following transplantation with sequential use of ALG and CsA. Other benefits to the renal recipient have also occurred with use of this immunotherapy protocol. Renal allograft survival for recipients of first, second, and third renal allografts has been higher than that generally reported with cyclosporine and prednisone alone. Rejection episodes have been infrequent during the first six months posttransplant, as 75% and 62% of first and second renal allograft recipients have remained rejection-free. Clinically significant infectious complications were infrequent. No cadaver recipient has developed a lymphoma. Moreover, the initial hospitalization following transplantation with sequential ALG/CsA has been short and generally uncomplicated. We conclude that sequential ALG/CsA following renal transplantation provides excellent early posttransplant immunosuppression while avoiding the nephrotoxic effects of CsA and also provides the steroid and infection-sparing benefits derived from maintenance CsA therapy.

Acute Kidney Injury↗
PubMed1987

Combined nephrotoxic effects of cyclosporine and endotoxin.

This study presents experimental evidence that cyclosporine (CsA) potentiates the nephrotoxicity of endotoxin. This study was motivated by clinical observations in 4 cyclosporine (CsA)-treated renal allograft recipients who developed severe, and sometimes irreversible, nephrotoxicity after infections. CsA or vehicle was administered intramuscularly to rabbits for 5 days, and subsequently both groups of animals received one dose of endotoxin intravenously. Compared with controls, CsA-treated animals demonstrated significantly higher elevations of blood urea nitrogen and serum creatinine 24 hr after endotoxin. By contrast, both groups of animals developed similar degrees of thrombocytopenia. Histologic evaluation of kidney tissues 24 hr after endotoxin revealed significantly greater tubular toxicity and a higher glomerular polymorphonuclear leukocyte (PMN) infiltration in CsA-treated animals. Semiquantitative scores of tubular damage correlated directly with the mean number of PMN/glomeruli in both groups of animals. Immunofluorescent microscopy of kidney tissues was negative for fibrinogen and for complement deposition in both CsA and control groups. We conclude that CsA enhances endotoxin nephrotoxicity in rabbits. This effect does not appear to be mediated by activation of coagulation factors. However, a role for PMN is suggested. CsA should be used with caution in patients with deteriorating renal function who are suspected of having severe bacterial infections.

Animals↗
PubMed1987

Frequency of human alloantigen-reactive T lymphocytes. II. Method for limiting dilution analysis of alloantigen-reactive helper T cells in human peripheral blood.

Quantitative immunologic techniques for analysis of human alloreactivity are currently lacking in transplantation immunology. We report a rapid, sensitive, and quantitative limiting dilution analysis technique that provides a minimal estimate of the number of peripheral blood mononuclear cells (PBMC) capable of secreting interleukin-2 (operationally defined as helpter T lymphocytes) when cultured in vitro with allogeneic PBMC bearing serologically identified MHC disparities. Using this LDA technique, we have estimated that approximately 1/500 to 1/2000 (0.2% to 0.05%) of the PBMC from various individuals can secrete IL-2 after in vitro contact with completely major-histocompatibility-complex-disparate PBMC. Under normal conditions the HTL frequency in human peripheral blood appears quite stable, based on serial analysis of HTL frequency in a healthy human donor. This LDA technique is more rapid and informative than the MLR, and may be useful for pretransplant evaluation and posttransplant monitoring of donor reactivity in transplant recipients.

Blood Cell Count↗
PubMed1987

A single center experience with cyclosporine in renal transplantation: Ohio State University 1983 to 1987.

1. Equivalent graft survival for both diabetic and nondiabetic recipients can be accomplished in haploidentical living-related donor transplants with either DST and posttransplant conventional immunosuppression or a CsA-prednisone protocol without pretransplant DST. 2. There is an 8% difference in one-year graft survival between living-related (91%) and first cadaveric (83%) donor renal transplants. At 2 years this difference is 12%. 3. In primary cadaveric donor transplants, only diabetic status and immediate graft nonfunction (ATN) proved significant determinants of graft survival. The degree of HLA-A, B, or DR match, transfusion, recipient age, or level of presensitization, were all variables that did not significantly correlate with outcome. 4. In the retransplanted population the level of presensitization and the presence of immediate graft nonfunction (ATN) proved significant variables on univariant analysis. The relationship between recipient presensitization as reflected in PRA and the incidence of ATN and the interplay of these 2 variables on graft survival strongly suggest an immunologically unique environment in the recipient undergoing retransplantation that negatively impacts on graft survival and that is not present following presensitization of primary cadaveric recipients.

Cadaver↗
PubMed1986

Clinical utility of serologic HLA-DR antigen identification using activated T lymphocytes.

Clinical experience has shown that it is often difficult to identify HLA-DR antigens on peripheral blood from long-term dialysis patients, leukemic patients, or blood in poor condition due to age of specimen or delivery conditions. We have found that we can accurately detect HLA-DR antigens on peripheral blood T cells that have been activated with PHA and expanded with commercially available Interleukin 2. An advantage of this technique is that a minimal number of peripheral blood cells is required at the initiation of T-cell activation. The expansion of T cells to a number sufficient for HLA-DR analysis requires 7 to 10 days. To test the validity of this protocol, we analyzed the HLA-DR antigens on a total of 13 normal donors using both conventional techniques and activated T cells. In every case, HLA-DR detection was identical by both methods, and no false positive or negative reactions were observed. Next, we used activated T cells to analyze the HLA-DR antigens in patients that had been difficult or impossible to DR type using conventional methods. We successfully identified HLA-DR antigens on 16 of 16 bone marrow transplant candidates who were previously untypable. We also identified HLA-DR antigens in all of the eight renal dialysis patients who had been untypable on several previous occasions. Subsequent phenotypic analysis of family members for those patients confirmed that the HLA-DR antigens genetically transmitted from family were detected by this method. In summary, we consider that activated T cells can be used effectively and reliably for analysis of HLA-DR antigens for patients who are otherwise difficult to type by conventional methods.

Blood Preservation↗
PubMed1986

Suppression of in vitro cell-mediated lympholysis generation by alloactivated lymphocytes. Examination of radioresistant suppressive activity.

We investigated the radioresistant (1000 rads) suppression of CML generation mediated by alloactivated murine splenocytes. Suppressive cells were generated in MLCs by stimulation of (A X 6R)F1 splenocytes with irradiated C57BL/10 splenocytes. Suppressive cells could lyse targets bearing H-2b alloantigens, but would not lyse parental B10.T(6R) or B10.A targets. Suppressive activity was detected by including the alloactivated (A X 6R)F1 cells in B10.T(6R) anti-B10.A(1R) MLCs. Relative to the suppressive (A X 6R)F1 cells, the B10.A(1R) lymphocytes display both parental and suppressor-inducing alloantigens. In the absence of a suppressive population, B10.A(1R) stimulators cause B10.T(6R) splenocytes to generate cytolytic activity specific for both H-2Db (suppressor-inducing) and H-2Kk (suppressor-borne) target determinants. The irradiated, alloactivated (A X 6R)F1 cells decrease the H-2Db-specific CML generated in this system, thus mediating apparent antigen-specific suppression. However, cytolytic activity concomitantly generated in the same culture against the unrelated H-2Kk target determinants is similarly reduced by the (A X 6R)F1 cells. Thus, radioresistant suppression by alloactivated splenocytes is not necessarily antigen-specific. The irradiated (A X 6R)F1 cells would not suppress the generation of H-2Kk-specific CTL in B10.T(6R) anti-B10.A MLCs. Hence, the irradiated (A X 6R)F1 cells can impede CML generation against third-party alloantigens if, and only if, those alloantigens are coexpressed with suppressor-inducing alloantigens on the stimulator cells in suppressed MLCs. Similar results were also obtained using a different histoincompatible lymphocyte combination. Since the pattern of suppressor specificity and the pattern of CTL specificity were identical and concomitant under these experimental conditions, these data are consistent with the hypothesis that radioresistant suppression by alloactivated lymphocytes can reflect coincidental in vitro cytolytic T cell function in vitro.

Animals↗
PubMed1986

In vivo mechanisms of alloreactivity. I. Frequency of donor-reactive cytotoxic T lymphocytes in sponge matrix allografts.

To study the development of alloreactive cytolytic T cells in vivo, C57BL/6 mice were implanted s.c. with polyurethane sponges bearing allogeneic (DBA/2) splenocytes. On various days thereafter, cells that had accumulated in these sponge grafts were tested for cytolytic activity against DBA/2 target cells in 51Cr-release assays, and for frequency of DBA/2-reactive CTL as determined by limiting dilution analysis (LDA). During these studies we found that LDA was consistently more efficient at detecting alloreactive CTL than the traditional 51Cr-release assays. As determined by LDA, sponge grafts initially infused with DBA/2 splenocytes acquired high levels of DBA/2-reactive CTL, while sponge grafts infused only with saline acquired few DBA/2-reactive CTL. DBA/2-reactive CTL first became detectable in sponge allografts approximately four days after implantation, and reached a maximal frequency by the 10th day after implantation. This frequency was maintained for at least the next seven days. In contrast, the ability of cellular infiltrates from sponge allografts to lyse DBA/2 target cells in 51Cr-release assays was not detectable until the 7th day after implantation, was optimal by the tenth day, but declined thereafter to lower levels, as observed on the 13th and 17th day after implantation. Since the frequency of CTL remains stable through the 17th day after implantation, this decline in cytolytic activity may indicate that donor-reactive CTL remain in sponge allografts, but they continue to differentiate to a noncytolytic status. We further observed that previous allosensitization with skin grafts markedly accelerates the accumulation of alloreactive CTL in sponge allografts. The mechanism that promotes more rapid accumulation of CTL in allosensitized sponge graft recipients remains to be established. Throughout these studies, we observed that even at peak development, donor reactive CTL are, at most, 0.2% of the cells recovered from sponge allografts. This raises some questions regarding not only the fundamental role of the CTL in allograft rejection, but also the role of the remaining 99.8% of the allograft-infiltrating cells.

Animals↗
PubMed1986

In vivo mechanisms of alloreactivity. II. Allospecificity of cytotoxic T lymphocytes in sponge matrix allografts as determined by limiting dilution analysis.

We have examined the frequency and alloantigen specificity of CTL that accumulate in sponge allografts (sponges seeded with allogeneic splenocytes) in sponge isografts (sponges seeded with syngeneic splenocytes), and in splenocyte-free sponge implants. Using limiting dilution analysis (LDA), we observed that sponge isografts and splenocyte-free sponge implants from C57BL/6 (H-2b) mice usually acquire small numbers of CTL (less than 250 cells per graft) with DBA/2 (H-2d)-reactivity or C3H/HeJ (H-2k)-reactivity. These alloreactive CTL are not detectable in conventional 51Cr-release assays, presumably because they are too infrequent and/or because they are inactive CTL precursors. When we examined the accumulation of alloreactive CTL in sponge allografts, we observed that DBA/2 sponge allografts from C57BL/6 recipients accumulate 10 to 100 times more DBA/2-reactive CTL than alloantigen-free sponge grafts. Nonetheless, these donor-reactive CTL rarely constitute more than 0.5% of the T cells recovered from sponge allografts, even at the peak of the rejection response. This raises questions concerning the remaining 99.5% of the allograft-infiltrating T cells. We were unable to detect by LDA any host-reactive CTL in sponge allografts, thus excluding the possibility that some of the remaining T cells were host-reactive CTL of donor origin which diluted graft-reactive T cells. However, using LDA we did detect a significant number of third-party (C3H/HeJ)-reactive CTL in sponge allografts, suggesting that the intense immune response at a graft site might facilitate indiscriminate recruitment of T lymphocytes. Alternatively, this enhanced third-party alloreactivity might reflect the proliferation of donor-reactive CTL with incidental crossreactivity for C3H/HeJ alloantigens. While testing these two alternatives, we observed that LDA cultures designed to detect third-party-reactive CTL could also support the growth of the in vivo-activated, donor-reactive CTL from sponge allografts; This compromised enumeration by LDA of the less frequent, third-party-reactive CTL by LDA. Although LDA is the only method that detects the growing population of third-party-reactive CTL in sponge allografts, technical restraints exclude LDA as a method of determining whether donor-reactive CTL and third-party-reactive CTL are separate or overlapping CTL subpopulations. Hence, it remains unclear if third-party-reactive CTL are a significant or insignificant proportion of the CTL that infiltrate sponge allografts.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗