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Biomedical subjects

M L Jordan

Publications and source records attributed to M L Jordan.

At least 91 records · Page 5Linked to original sources
PubMed1992

Pediatric renal transplantation under FK-506 immunosuppression.

Renal transplantation (11 cadaveric and 1 living-related donor) was performed in 12 pediatric recipients (mean age 10.8 years) under FK-506 immunosuppression in combination with prednisone therapy. At a mean followup of 6.1 months, patient and graft survival rates were 100% and 92%, respectively. The only graft loss was due to the recurrent hemolytic uremic syndrome 4 days after transplantation. In the functioning grafts the mean serum creatinine is 1.59 +/- 1.27 mg./dl. and the mean blood urea nitrogen is 36.3 +/- 24.6 mg./dl. Three patients take no prednisone, 5 are receiving 0.15 to 0.25 mg./kg. per day and 3 are taking 0.35 to 0.5 mg./kg. per day. There was a total of 8 rejection episodes in 5 patients. All rejection episodes were successfully reversed. Complications of transplantation included an episode of seizures in 1 patient, cytomegalovirus infection in 1 and steroid-induced diabetes mellitus in 1. Since pediatric transplant recipients are a group in whom the reduction or elimination of steroids is highly desirable, FK-506 immunosuppression may be particularly suited for use in this population.

Adolescent↗
PubMed1991

Evidence that protein kinase C regulates allosensitized T lymphocyte function.

The role of second messengers in the response of alloactivated T cells to growth factors (e.g., interleukin-2) is unknown. We have previously found that intracellular calcium may be an important T-cell alloactivation marker. To determine whether protein kinase C (PKC) is also involved in allosensitized T cell function, we studied the effects of the PKC agonists phorbol 12-myristate 13-acetate (PMA), mezerein (MEZ), and 1-oleoyl-2-acetylglycerol (OAG) and the PKC antagonists phloretin and D-sphingosine on the in vitro proliferation and migration of allosensitized cells from a C57BL/6 anti-DBA/2J mixed leukocyte culture (MLC). At 0.01-1.0 microgram/ml, PMA, a potent stimulant of PKC, exerted profound stimulatory effects on secondary MLC supernatant (2 degrees SN)-induced proliferation of allosensitized T cells (132-200% increase, P less than 0.01). Both MEZ and OAG are less potent activators of PKC than PMA but also stimulated T cell proliferation (132-152% of control, P less than 0.01). The PKC antagonists phloretin and D-sphingosine both inhibited proliferation by greater than 50% at 1.0-10.0 microM (P less than 0.01). Further experiments showed that these agents exert similar effects on in vitro T cell locomotion in a Boyden chamber assay. These data indicate that PKC activation may be an important component of allosensitized T cell proliferation and locomotion and may constitute a pathway by which T cell function may be modified in the allograft response.

Animals↗
PubMed1991

Highly sensitized patients with delayed graft function: a management protocol.

The postoperative management of the highly sensitized renal transplant recipient with delayed graft function on cyclosporine is complicated. Allografts with delayed graft function are reported to have a 20 to 30% poorer 1-year survival than allografts without delayed graft function. Several factors may be implicated in this poorer 1-year survival. A decrease in or cessation of cyclosporine dosage frequently is used in an attempt to minimize nephrotoxicity. Such under-immunosuppression can result in irreversible rejection. Occasionally, a pessimistic view of the prognosis for the transplant may result in early abandonment of the allograft with discontinuation of immunosuppression and allograft nephrectomy. We report on 3 highly sensitized patients whose kidneys had delayed graft function and were deliberately maintained on high doses of cyclosporine throughout the period of delayed graft function. Each graft achieved function (2, 4 and 5 months) after transplantation. The serum creatinine levels 20, 28 and 38 months after transplantation were 2.7, 2.0 and 1.0 mg./dl., respectively. We suggest that the maintenance of high cyclosporine levels throughout the delayed graft function period is useful in highly sensitized recipients and was an important factor in their successful outcome. A management protocol for such patients is proposed.

Adolescent↗
PubMed1991

Sustained increases in cytosolic calcium during T lymphocyte allosensitization, proliferation, and acquisition of locomotor function.

Activation of resting T cells is accompanied by an increase in cytosolic calcium ([Ca2+]i). However, the role of [Ca2+]i in the effector function of allosensitized cells, and how this may affect the evolution of the allograft response is unknown. To evaluate this more directly, we determined [Ca2+]i in both unsensitized T cells (C57BL/6 murine thymocytes) and in allosensitized T cells derived from different days of a C57BL/6 anti-DBA/2J mixed leukocyte culture. To correlate potential changes in [Ca2+]i with concomitant development of T cell effector function, the [Ca2+]i, proliferation (3HTdR uptake), and random locomotion (in vitro modified Boyden chamber assay) of the same cells was assayed simultaneously. Allosensitized T cells exhibited higher (P less than 0.05) [Ca2+]i than unsensitized thymocytes on all days of culture tested. Further, there was a progressive rise in [Ca2+]i during the course of allosensitization. Con A stimulated an increase in [Ca2+]i over basal levels (P less than .05) for all cell types. A rise in [Ca2+]i preceded the onset of maximal allosensitized T cell proliferation (which peaked at day 7) and this continued to increase even after completion of DNA synthesis. In contrast, optimal T cell locomotion coincided with maximal [Ca2+]i, well after cell division had occurred. Prostaglandin E2, a known inhibitor of lymphocyte function, did not alter either basal or Con A-stimulated [Ca2+]i in thymocytes or MLC cells. These results indicate that [Ca2+]i signaling persists long after initial T lymphocyte alloactivation, and is maintained during DNA synthesis and acquisition of locomotor capacity. Furthermore, the inhibitory effects of PGE2 on allosensitized T lymphocyte function may be mediated by a calcium-independent mechanism.

Animals↗
PubMed1990

The role of cold ischemia in a provincial organ-sharing program in the cyclosporine era.

Prolonged cold ischemia has been associated with impaired early cadaver renal allograft function. The role of CsA in potentiating these effects is not well understood, but CsA has been implicated in promoting delayed graft function and potentiating renal ischemic injury. In order to establish whether CsA is safely tolerated by kidneys subjected to protracted cold ischemia, we examined patient and graft outcome in a series of 1081 patients receiving cadaver-kidney transplants over an 8-year period (1981-1988). All patients received a standard immunosuppressive regimen that included CsA. Overall actuarial 1-year patient and graft survival rates were 96% and 80%, respectively. Renal preservation was achieved either by pulsatile perfusion (n = 261, 24%) or simple cold storage (n = 820, 76%). Results were analyzed according to total cold ischemic time as follows: 0-23 hr (n = 512; range, 0-23.9 hr); 24-35 hr (n = 380; range, 24.0-35.9 hr); 36-47 hr (n = 161; range, 36.0-47.7 hr); greater than or equal to 48 hr (n = 28; range, 48.0-70.6 hr). These groups did not differ significantly in recipient age, sex, incidence of diabetes, number of pretransplant blood transfusions, level of presensitization, or HLA match. There were no differences in overall actuarial 1-year patient or graft survival rates, incidence of rejection, or renal function at 1 year. There was a higher incidence of impaired early graft function for kidneys preserved greater than or equal to 48 hr, but eventual graft outcome, including serum creatinine at 1 year, was unchanged. Delayed introduction of CsA resulted in improved 1-year graft survival (84.4% vs. 74.7%, P less than 0.05) compared to CsA treatment begun at the time of transplantation ("initial CsA"). This improvement was present regardless of total cold ischemia time. The incidence of permanent graft nonfunction, which has been previously reported to increase with CsA therapy, was influenced by the timing of CsA therapy (initial: 12%; delayed: 3%, P less than 0.05) but was not affected by duration of cold ischemia. Thus, safe preservation of cadaver kidneys for up to 70 h can be achieved by standard techniques even when CsA is incorporated into the immunosuppressive regimen. The most important determinants of graft survival in these patients are the timing of CsA therapy and the presence of early graft function, not the duration of renal preservation.

Blood Group Incompatibility↗
PubMed1989

The University of Pittsburgh: a three and three-quarter-year experience with cadaveric renal transplantation under the point system.

Eight hundred and sixty kidney transplants were performed at the University of Pittsburgh over a 3.75-year period between January 1, 1986 and October 19, 1989. Recipient selection was by means of a computerized point system designed to allocate organs equitably. Ninety-three percent 1-year patient survival and 74% 1-year graft survival were obtained in the overall group; 80% 1-year graft survival was obtained in patients receiving immunosuppression with CsA, azathioprine, and prednisone. These data serve as a measure of what can be achieved with an equitably based allocation system and can serve as a basis of comparison with other allocation protocols or new immunosuppressive regimens.

Adult↗
PubMed1988

Characterization of natural killer activity in sponge matrix allografts.

NK cell activity, defined by the ability of infiltrating host cells to lyse the YAC-1 tumor target, can be detected in sponge matrix allografts across all genetic barriers tested. Nonspecific tumor cell killing cannot be detected either within bulk populations of host-infiltrating cells or in populations enriched for non-adherent lymphocytes. NK activity is also detected in cells infiltrating a syngeneic sponge matrix graft although to a much lesser extent than an allogeneic graft. NK cell functional activity at the graft site precedes the appearance of alloimmune CTL by several days. The surface phenotype of the NK cell is Thy-1.2+ and L3T4- as determined by depleting the various subpopulations with antibody and C. Systemic treatment of sponge-bearing animals with repeated injections of anti-asialo GM1 (AGM1) results in inhibition of both NK activity and CTL activity recovered from the graft on days 5 to 9 after grafting, but on days 11 to 13 after grafting both NK activity and CTL activity are found within the sponge graft. Treatment of sponge-associated cells with anti-AGM1 in vitro or intrasponge injection of anti-AGM1 at various times after grafting eliminates NK activity more readily than alloimmune CTL activity. The intimate association observed between NK cells and alloimmune CTL at the graft site prompts further investigation into the role of NK cells in the allograft response.

Animals↗
PubMed1988

Allosensitized helper and cytotoxic T-lymphocyte clones differentially modulate endotoxin-stimulated macrophage function.

Alterations in macrophage function may render the immunocompromised host more susceptible to infectious complications. Although allograft recipients are at increased risk of infection primarily because of pharmacologic immunosuppression, whether the process of allosensitization per se alters this risk is unknown. We therefore studied the effects of cloned allosensitized murine helper or cytotoxic T cells on both interleukin 1 (IL-1) and prostaglandin E2 (PGE2) production by syngeneic resident murine peritoneal macrophages. Endotoxin (lipopolysaccharide [LPS]) stimulated both IL-1 and PGE2 production in macrophages. Cloned T cells alone, with or without LPS pretreatment, produced neither IL-1 nor PGE2. After 48 hours of coculture with LPS-treated macrophages, cloned helper cells augmented IL-1 release by macrophages but inhibited PGE2 production. In contrast, cytotoxic T cells not only reduced IL-1 production by macrophages but also potentiated PGE2 release. These effects were not observed when macrophages were not first exposed to LPS. Thus, endotoxin renders macrophages more susceptible to allosensitized "help" (increases IL-1, decreases PGE2) or "suppression" (decreases IL-1, increases PGE2) by cytotoxic T cells. We hypothesize that, even in the absence of immunosuppression, the process of allosensitization itself may modulate the response to sepsis by altering host macrophage function.

Animals↗