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Biomedical subjects

J H Helderman

Publications and source records attributed to J H Helderman.

At least 55 records · Page 3Linked to original sources
PubMed1994

Chronic immunosuppression of the renal transplant patient.

The advent of potent immunosuppressive drugs to prevent rejection has led to a phenomenal improvement in renal transplant results increasing spectacularly the number of transplant recipients to arrive in the transplant clinic who remain for many years. This has engendered a series of questions about the most appropriate cyclosporine dosing for these patients that prevents rejection while avoiding toxicity. Three separate issues were analyzed: the most appropriate combination strategy with cyclosporine as a base "double" or "triple" therapy; the possibility of conversion from regimens containing cyclosporine to those devoid of it; and the optimal cyclosporine dose for a maintenance regimen. A meta-analysis of seven individual prospective and randomized trials of double versus triple therapy encompassing 1,080 patients revealed no statistical difference between the two regimens in terms of graft survival at 1 or 5 yr, patient survival, the rejection rate per patient, or the infection rate. In an analysis of 17 separate studies in which conversion away from cyclosporine was attempted, in 629 individuals with 702 individuals left on cyclosporine as controls, a significant risk of acute rejection (P < 0.001) was found in the withdrawn group without evidence of improved graft survival. Certain factors such as previous rejection, race, and degree of reactivity predicted even more rejection in the withdrawn group. Analyzing six separate studies of renal transplant recipients maintained on cyclosporine for up to 5 yr with renal functional stability, one can conclude that a dose of approximately 4.0 mg/kg per day is optimal. Because of variant pharmacokinetics or concomitant medicines, blood levels can confirm a therapeutic concentration with this target dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Trials as Topic↗
PubMed1993

Immunosuppressive drugs and their effects.

The growing success of organ transplantation for the treatment of diabetes mellitus and end-stage renal, heart, lung, and liver disease is attributable, in part, to improvements in immunosuppressive regimens. This article reviews the immune response and the mechanism by which many immunosuppressants exert their effects. Immunosuppressants discussed include azathioprine, glucocorticoids, cyclosporine A, cyclosporine G, FK506, rapamycin, mycophenolic acid, mycophenolate mofetil (RS-61443), mizoribine (bredinin), brequinar sodium, and deoxyspergualine. The efficacy and nonspecificity of these agents has led to significant side effects from their use, which can be predicted based on their mechanisms of action. The development and use of more specific immunosuppressants or the design of protocols, which would induce organ tolerance, may result in long-term organ survival without infectious or malignant complications.

Clinical Protocols↗
PubMed1992

Identification of a monocyte-derived factor which regulates synthesis of insulin receptors on activated T-lymphocytes (MIRRF).

The regulation of the insulin receptor on the activated T-lymphocyte was studied. It has been previously shown that the monocyte with its constitutive insulin receptor can signal the quiescent T-lymphocyte with respect to ambient insulin concentration which regulates the copies of insulin receptors synthesized during the lymphocyte activation event. In this communication it is shown that the vehicle by which the monocyte signals the T-lymphocyte is a soluble, small molecular weight protein. Initially a bioassay was established to test the putative monocyte-derived factor in which freshly prepared purified populations of monocytes were incubated with insulin, extensively washed, and replated with lymphocytes in microwells or across a 3 microns filter from lymphocytes using the appearance of insulin receptors on T lymphocytes responding to lectin as measured by a radioligand binding assay as the outcome variable. Dose response and time course relationships were established to develop the ideal conditions for the bioassay. It was shown that the monocyte-derived insulin receptor regulatory factor (MIRRF) could be readily detected in conditioned medium of insulin-incubated and then washed monocytes as a starting point for attempts at later purification. Using rats fed an essential fatty acid deficient diet (EFAD), incapable of generating standard prostanoids, it was demonstrated that the MIRRF was readily detectable in our standard bioassay revealing that the factor was not a member of the arachidonic acid family. Lastly, it was shown that MIRRF is cycloheximide sensitive and either is a protein or requires protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

The strong correlation of cytotoxic T lymphocyte-specific serine protease gene transcripts with renal allograft rejection.

Several immune mechanisms are likely to be responsible for renal allograft rejection. The relative importance of delayed-type hypersensitivity versus cytotoxic T lymphocytes is controversial. We analyzed human renal allografts biopsies for intragraft expression of IL-1 beta, IL-6, and TNF alpha genes--putative mediators of DTH--as well as IL-2, IL-2 receptor (R) beta, and a CTL-specific serine protease gene. Total RNA was extracted from tissue samples and the mRNA fraction was converted to cDNA using oligo dT and reverse transcriptase. Then cDNA was amplified by the polymerase chain reaction (PCR) for 35 cycles using specific oligonucleotide primers. Each PCR analysis included beta-actin oligonucleotide primers to coamplify this constitutively expressed gene as an internal control. A total of 24 core allograft biopsies were studied and classified into a 3 histological categories: acute cellular rejection, equivocal components of rejection, and no evidence of rejection. There was no statistically significant difference in beta-actin expression among these histologic categories (P greater than 0.08). Interestingly, in this sample size, no significant difference was found between rejecting and nonrejecting samples for transcripts of any of the cytokines or IL-2R beta mRNAs. Apparently, DTH-like mechanisms are present in all allografts. However, detection of CTL-specific serine protease gene expression was almost exclusive to rejecting samples (P less than 0.003). These findings suggest that activation of CTLs play an active, but hardly exclusive, role as effectors of graft dysfunction in the rejection process. While this study does not define the relative importance of the genes examined, it does suggest that evidence of CTL-specific serine protease expression may provide a means of monitoring for rejection episodes or as a diagnostic aid when conventional diagnostic criteria are not conclusive.

Adolescent↗
PubMed1992

The effect of polyimmune gammaglobulin for prophylaxis against reactivation cytomegalovirus infection in kidney and kidney/pancreas transplant recipients.

Cytomegalovirus (CMV) remains the most important infection in the renal transplant recipient. Few data are available that provide guidance for approaches that seek to reduce the reactivation of latent disease after transplantation. To test the efficacy of polyimmune gammaglobulin in kidney and kidney/pancreas transplantation, consenting recipients with serologic evidence of previous CMV disease were randomized to receive i.v. polyimmune gammaglobulin (500 mg/kg) within 3 days of transplant with 250 mg/kg at weeks 1, 2, 4, and 6 or no prophylaxis. Both groups received identical induction and rejection immunosuppressive therapy. Polyimmune gammaglobulin prophylaxis reduced CMV reactivation infections. The incidence of reactivation infections was half in patients receiving Nashville/rabbit antithymocyte serum (N/R-ATS) compared with those receiving monoclonal anti-CD-3 therapy. Patients receiving polyimmune gammaglobulin along with N/R-ATS had an incidence of infection of only 10%. Reactivation infections were twice as common in patients who had primary nonfunction and nearly three times as common in patients with acute rejection. Both risk factors were associated with longer anti-T-cell therapy. Polyimmune gammaglobulin prophylaxis should be considered in transplant patients with previous CMV exposure who will be receiving prolonged anti-T-cell therapy because of acute rejection or primary nonfunction.

Adult↗
PubMed1992

The impact of acemannan on the generation and function of cytotoxic T-lymphocytes.

Acemannan, an antiviral agent with immune enhancement capabilities, was studied for its impact on cytotoxic T-lymphocyte (Tc) function generated in response to alloantigen. To investigate whether acemannan directly stimulated the generation of Tc from primary mixed lymphocyte cultures (MLC), the drug was added at the initiation of the MLC. There was a dose-related, statistical increase in killer T-cell generation produced by acemannan in the clinically relevant dose range. The lowest test dose of the drug (2.6 x 10(-9) M) increased chromium release nearly two-fold; the 2.6 x 10(-8) M dose gave a maximal 3.5 fold increase in cytotoxic T-cells. To study whether acemannan enhanced the capacity of Tc once generated to alloantigen to destroy targets bearing the sensitizing antigens, MLR were established in the absence of any drug. Acemannan at the two highest doses increased the functional capacity of Tc to destroy target cells to which they had been sensitized in the MLR. To control for the possibility that acemannan was directly cytotoxic to target cells, targets were incubated alone with drug and without sensitized killer T-cells. No dose of acemannan was found to be cytotoxic to these cells. In conclusion, acemannan did enhance the generation of cytotoxic T-cells when added at the initiation of the MLR. When acemannan was added at the completion of allostimulation, an increase of almost 50% killing by Tc was also observed. These effects can not be explained by direct drug related toxicity and suggest a functional correlate to the previously described immune enhancing properties of the agent. As this drug is being tested for the treatment of HIV infections, these data provide at least one immunologic mechanism by which acemannan may be clinically salutory.

Adjuvants, Immunologic↗
PubMed1992

Colonic screening prior to renal transplantation and its impact on post-transplant colonic complications.

Colonic complications after renal transplantation are uncommon but have a high mortality rate. Some have recommended colonic screening in patients over 50 years of age prior to transplantation to lessen the impact of colonic diverticular disease. We report our 9-year experience of colonic screening for diverticular disease in potential recipients over the age of 50 and compare these results to the overall colonic complication rate in the same time period. From 1981-1990, 1186 renal transplants in 1019 patients were performed, during which time all potential recipients over the age of 50 yr were required to undergo colon evaluation prior to transplantation. Twenty cases of diverticular disease were found with more than a quarter of the cases in patients with adult polycystic disease. All underwent renal transplantation without a pre-transplant colectomy, and none had post transplant symptomatic colon disease. During that same time period a total of 14 colonic complications requiring surgical intervention were encountered with a mortality rate of 40%. Acute diverticulitis occurred in 5 patients, all of whom were over 50 yr of age, on low-dose immunosuppression, and in most cases it occurred remotely after transplantation. Colonic dysplasia/neoplasia also occurred remotely after transplantation in 2 patients over the age of 50. Cytomegalovirus (CMV) colitis was the next most common complication, accounting for 3 cases. This complication, which occurred in younger patients, was associated with high-dose steroid immunosuppression and had a high mortality rate, in spite of surgical intervention.(ABSTRACT TRUNCATED AT 250 WORDS)

Colitis↗
PubMed1991

Immunobiological consequence of regulation of insulin receptor on alloactivated lymphocytes in normal and obese subjects.

Acute manipulations of insulin in vivo regulate the display of insulin receptors induced on activated T lymphocytes after presentation of alloantigen. This study explored the immunobiological consequences of regulation of insulin-receptor display by acute manipulations of insulin achieved during the hyperinsulinemic-euglycemic clamp in healthy normal individuals and obese subjects. T lymphocytes were isolated at 0, 1, and 4 h of hyperinsulinemia from seven normal volunteers and seven obese individuals and studied for their capacity to 1) synthesize a complement of insulin receptors on cell membrane, 2) respond to alloantigen in the mixed-lymphocyte culture (an immunologic activity unrelated to manipulations in insulin concentrations in complete medium), and 3) respond to the lymphocyte-mediated cytotoxicity reaction (an immunologic activity known to be modulated by insulin). In the face of a reduction in receptor numbers to 25% of baseline in normal individuals, alloreactivity in the mixed-lymphocyte culture was not affected (95 +/- 9% of time 0 after 4 h of hyperinsulinemia), whereas lymphocyte-mediated cytotoxicity fell from 14 +/- 4 at time 0 to 2 +/- 2% sp Cr release (P less than 0.02). Hyperinsulinemia achieved by the clamp in seven obese subjects did not alter the synthesis of insulin receptors on cell membrane after presentation of alloantigen. In the absence of further reduction of insulin-receptor membrane display, neither the mixed-lymphocyte culture nor lymphocyte-mediated cytotoxicity reaction was affected. It is concluded that those immunologic activities of lymphocytes that can be modulated by insulin are affected by regulation of insulin-receptor display on activated lymphocytes. Therefore, receptor regulation is not effete but carries significant immunologic consequence.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗