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Biomedical subjects

P A Taylor

Publications and source records attributed to P A Taylor.

At least 19 recordsLinked to original sources
PubMed1995

In utero transfer of adult bone marrow cells into recipients with severe combined immunodeficiency disorder yields lymphoid progeny with T- and B-cell functional capabilities.

To determine if in utero transplantation could restore the immune system of mice with a severe combined immunodeficiency (SCID) disorder, C57BL/6Sz-scid/scid fetuses were injected on day 14/15 of gestation with adult congenic donor bone marrow (BM) cells. Congenic BM engrafted in one of eight (13%) recipients. Reconstitution of both lymphoid and nonlymphoid lineages was observed. In vitro and in vivo T-cell function was documented. Stem cells were shown to have engrafted by secondary transfer studies. When fully allogeneic C57BL/6 (H-2b) or B10.BR (H-2k) adult. BM cells were given to C.B-17-scid/scid (H-2d) fetal recipients, 15 of 54 (28%) recipients had evidence of engraftment, with up to 76% of peripheral blood (PB) being of in utero donor BM origin on day 131 postnatally. In all mice with persistent leukocyte engraftment, T- and B-lymphoid cells were entirely of donor origin. Donor T cells were tolerant to host but not third party alloantigens as measured in vitro. In vivo, T-cell function appeared intact. Although most mice had lower levels of B-cell engraftment than T-cell engraftment, mice with > or = 10% B cells were able to produce normal levels of IgM. Despite transplantation of fully allogeneic BM cells, stem cell engraftment could be demonstrated by secondary transfer of BM cells into lethally irradiated recipients that were congenic to the original in utero donor BM source. These data indicate that adult BM cells, even those fully allogeneic with the fetal recipient, can give rise to progeny with multilineage potential, which leads to restoration of T-cell and B-cell function.

Animals↗
PubMed1995

Therapy for ongoing graft-versus-host disease induced across the major or minor histocompatibility barrier in mice with anti-CD3F(ab')2-ricin toxin A chain immunotoxin.

A new pharmacologic agent, anti-CD3F(ab')2-ricin toxin A chain (RTA), was synthesized for the purpose of targeting T cells and as a means of treating established graft-versus-host disease (GVHD). The Fc region of anti-CD3 monoclonal antibody (MoAb) was removed to prevent its ability to activate T cells. The resulting F(ab')2 fragments were conjugated to deglycosylated RTA (dgRTA), a catalytic and potent phytotoxin. The resulting immunotoxin (IT) was potent (greater than 95% inhibition) and selective in inhibiting T-cell mitogenesis in vitro. In vivo, the IT depleted 80% of T cells in mice receiving bone marrow (BM) transplants. Transplantation in an aggressive acute GVHD model using C57BL/6 donor cells and H-2 disparate B10.BR recipients resulted in an infiltration of CD3-expressing cells and a median survival time (MST) of 20 to 30 days. A 5-day course of anti-CD3F(ab')2-RTA (30 micrograms/d intraperitoneally) beginning 7 days after GVHD induction was beneficial in treating established GVHD in these mice, as evidenced by significantly prolonged survival (MST, greater than 80 days), superior mean weight values, and improved clinical appearance. Neither intact anti-CD3, unconjugated anti-CD3 F(ab')2 fragments, nor a mixture of anti-CD4 and anti-CD8 MoAbs (which are highly effective in prophylactic models) were as effective. F(ab')2 fragments made from anti-Lyt-1 (the murine homologue of human anti-CD5) linked to RTA were also not effective, despite the fact that both anti-CD3F(ab')2-RTA and anti-Lyt-1F(ab')2-RTA had similar half-lives of about 9 hours. The IT also increased MST in two aggressive models of GVHD across non-H-2 minor histocompatibility barriers, indicating that the usefulness of anti-CD3F(ab')2-dgRTA is not limited to a single-strain combination. This agent should be further investigated as an alternative to current strategies for treating steroid refractory GVHD.

Animals↗
PubMed1995

Coblockade of the LFA1:ICAM and CD28/CTLA4:B7 pathways is a highly effective means of preventing acute lethal graft-versus-host disease induced by fully major histocompatibility complex-disparate donor grafts.

We have developed an in vitro system in which C57BL/6 donor splenocytes are exposed to B10.BR host alloantigens in the context of deficient CD28:B7 signaling as a means of preventing graft-versus-host disease (GVHD). Although 54% to 82% of MLR alloresponse was inhibited by cytotoxic T-lymphocyte antigen 4 (CTLA4)-Ig treatment of host stimulator cells, treated splenocytes were still capable of causing GVHD when infused in vivo. By adding anti-leukocyte function antigen 1 (anti-LFA1) antibody to hCTLA4-Ig in vitro to coblock the LFA1:intercellular adhesion molecule (ICAM) signaling, splenic alloresponse was inhibited by > or = 89%, yet GVHD induction capabilities were retained. Because antigen-primed cells might be more susceptible to CD28:B7 blockade, we investigated whether hCTLA4-Ig alone, anti-LFA1 antibody alone, or the combination of both added to donor-antihost in vitro primed cells could reduce GVHD. To facilitate hyporesponsiveness induction and to block B7 and ICAM ligands that are upregulated during GVHD, these reagents were also administered to recipients post-BMT. We have shown that hCTLA4-Ig plus anti-LFA1 antibody is highly effective in preventing GVHD-induced lethality (88% to 100% of treated mice surviving versus 0% to 28% of controls surviving). For optimal prevention, both hCTLA4-Ig and anti-LFA1 must be used in vitro in the context of donor-antihost primed splenocytes and continued in vivo. This in vitro-in vivo combined approach was associated with donor engraftment, and recipients were not globally immunosuppressed. We conclude that blocking both the CD28/B7 and the LFA1:ICAM pathways are critical to effective GVHD prevention and may offer advantages to in vitro donor T-cell removal.

Abatacept↗
PubMed1995

Adult bone marrow-derived pluripotent hematopoietic stem cells are engraftable when transferred in utero into moderately anemic fetal recipients.

We have used W41/W41 (C57BL/6-Ly 5.1, Gpi-1b) anemic mice and a newly developed double congenic donor strain (C57BL/6-Ly 5.2, Gpi-1a) to determine if adult bone marrow (BM) injected in utero could provide stem cell engraftment. Of 38 fetuses injected intraperitoneally on day 13/14 of gestation with donor BM cells, 17 (47%) were live-born. On day 6, 12% had erythroid engraftment. On day 59, in 50% (8/16) of mice, 50% to 75% of erythroid cells, 42% of T cells, 5% of B cells, and 26% of granulocytes in the peripheral blood (PB) were derived from the in utero-injected donor BM. At 141 days, thymic, splenic, lymph node, BM, and PB chimerism studies showed that 57% to 80% of T cells, 10% to 15% of B cells, and 27% to 43% of granulocytes were of donor origin. At this time, BM was injected into irradiated secondary recipients. On day 104 posttransfer, a mean 23% of T cells, 8% of B cells, and 40% of granulocytes were derived from the in utero donor BM. These data indicate that adult BM has hierarchical engraftment capabilities in W41/W41 mice and prove that stem cells are engraftable in utero.

Animals↗
PubMed1995

Interleukin-10 administration decreases survival in murine recipients of major histocompatibility complex disparate donor bone marrow grafts.

Studies in mice and humans have indicated that the predominance of interleukin-4 (IL-4)- and IL-10-producing T-helper type 2 (Th2) cells may serve to downregulate acute graft-versus-host disease (GVHD) reactions, whereas IL-2-producing Th1 cells have been implicated in facilitating acute GVHD. We explored the possibility that the in vivo infusion of IL-10 would inhibit acute GVHD induced by fully allogeneic donor grafts. Unexpectedly, IL-10 infusions resulted in a dose-dependent increase in GVHD-induced mortality. The acceleration of lethal GVHD by IL-10 occurred in irradiated recipients of T-cell-depleted bone marrow (BM) plus 5, 15, or 25 x 10(6) splenocytes but did not influence the post-BM transplantation (post-BMT) survival rate of recipients of BM without splenocytes, suggesting that the IL-10 effects were not due to toxicity. Antimurine IL-10-neutralizing monoclonal antibody injections, administered to diminish endogenous IL-10, reduced GVHD-associated mortality and improved the clinical appearance of the recipients. For BM graft rejection studies, IL-10 was infused into sublethally irradiated recipients of anti-Thy 1.2 + C' T-cell-depleted, fully allogeneic BM grafts. In a short-term (day 7) in vivo assay, IL-10 infusions significantly inhibited allogeneic (but not syngeneic) BM proliferation in vivo, indicative of increased graft rejection. In long-term chimerism experiments, IL-10 infusions caused a significant increase in early post-BMT mortality caused by a profound anemia typically associated with graft rejection and aplasia. A slightly higher irradiation dose (650 cGy v 600 cGy) eliminated the anemia but did not reverse the graft rejection process associated with IL-10 administration. We conclude that the in vivo infusion of exogenous IL-10 in recipients of fully allogeneic donor grafts results in accelerated GVHD and graft rejection in the strain combinations tested to date.

Animals↗
PubMed1995

Effect of IL-7 or IL-4 on reconstitution of donor lymphoid cells in congenic murine bone marrow transplantation.

IL-7 and IL-4 are known to influence the growth of cells of the lymphoid lineage. In this study, we investigated the effects of in vivo administration of IL-7 or IL-4 in mice subjected to congenic BM transplant. C57BL/6 Ly5.1+ mice were subjected to TBI, followed by transfer of B and T cell-depleted BM from C57BL/6 Ly5.2+ donor mice. Recipient mice were implanted with 14-day miniosmotic pumps that delivered IL-7, IL-4 or PBS and were examined for reconstitution of lymphoid cells using flow cytometry on different days. We observed no significant difference in the number of splenocytes, thymocytes and PBLs between recipient mice administered with cytokines or normal control mice. However, we observed that IL-4 infusion resulted in appearance of increased numbers of donor CD23+B220+ cells and also donor cells expressing Fc receptors for IgM (Fc micro R) and B220. Since CD23 is present only on mature B cells, our data demonstrate that following BMT, IL-4 treatment results in the development of more mature B cells compared to control mice. Additionally, we observed that IL-7 infusion resulted in significantly decreased expression of donor sIgM+B220+ cells. However, the effects of IL-7 or IL-4 were observed when the cytokines were actively administered and rapidly abated upon cessation of cytokine therapy.

Animals↗
PubMed1994

FK506 inhibits graft-versus-host disease and bone marrow graft rejection in murine recipients of MHC disparate donor grafts by interfering with mature peripheral T cell expansion post-transplantation.

FK506 was evaluated as the sole graft-vs-host disease (GVHD) preventive agent in murine recipients of fully allogeneic donor grafts. FK506 (36 mg/kg given as a suspension on days 0 through 13, then three times per wk through day 29 post-bone marrow transplantation (BMT)) reproducibly led to 50 to 90% of FK506-treated recipients surviving a 60- to 103-day observation period. High doses of cyclosporin A did not protect mice from lethal GVHD. A kinetic study performed in mice that received FK506 demonstrated that mature donor CD3+, CD4+, and CD8+ T cells in the spleen were each reduced by > or = 64%, as compared with vehicle-treated control mice, although this effect was short lived. Thymic reconstitution studies revealed a remarkable decrease in mature CD4+ cells and cells expressing the activation Ag, CD69. In contrast, less mature CD4+8+ thymocytes were not reduced significantly and total thymocyte numbers were only marginally decreased. The fact that peripheral reconstitution of CD4+8- or CD8+4- T cells was impaired significantly at this time indicated that FK506 had a major effect on thymic maturation and/or thymic emigration. In two models specifically designed to study alloengraftment, recipients of pan-T cell-depleted (TCD) donor marrow and FK506 were noted to have accelerated hemopoietic recovery and augmented long-term multilineage peripheral blood alloengraftment, in marked contrast to controls (86 to 97% mean donor cells vs 0% in controls for all lineages). These data demonstrate that FK506 prevents GVHD and graft rejection in vivo by inhibiting mature T cell expansion post-BMT.

Animals↗
PubMed1994

In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice.

We tested whether the in vivo infusion of recombinant, soluble CTLA4 fused with Ig heavy chains, as a surrogate ligand used to block CD28/CTLA4 T-cell costimulation, could prevent efficient T-cell activation and thereby reduce graft-versus-host disease (GVHD). Lethally irradiated B10.BR recipients of major histocompatibility complex disparate C57BL/6 donor grafts received intraperitoneal injections of human CTLA4-Ig (hCTLA4-Ig) or murine CTLA4-Ig (mCTLA4-Ig) in various doses and schedules beginning on day -1 or day 0 of bone marrow transplantation (BMT). In all five experiments, recipients of CTLA4-Ig had a significantly higher actuarial survival rate compared to mice injected with an irrelevant antibody control (L6) or saline alone. Survival rates in recipients of hL6 or PBS were 0% at 29 to 45 days post-BMT. In recipients of CTLA4-Ig, survival rates were as high as 63% mice surviving 3 months post-BMT. However, protection was somewhat variable and recipients of CTLA4-Ig were not GVHD-free by body weight, clinical appearance, and histopathologic examination. There were no significant differences in the survival rates in comparing injection dose, injection duration, or species of CTLA4-Ig (hCTLA4-Ig v mCTLA4-Ig). Splenic and peripheral blood flow cytometry studies of long-term hCTLA4-Ig-injected survivors showed a significant peripheral B-cell and CD4+ T-cell lymphopenia, consistent with GVHD. A kinetic study of splenic reconstitution was performed in mice that received hCTLA4-Ig and showed that mature splenic localized CD8+ T-cell repopulation was not significantly different in recipients of hCTLA4-Ig compared with hL6, despite the significant increase in actuarial survival rate in that experiment. These data suggest that the beneficial effect of hCTLA4-Ig on survival is not mediated by interfering with mature donor-derived T-cell repopulation post-BMT. Neither hCTLA4-Ig nor mCTLA4-Ig interfered with hematopoietic recovery post-BMT. We conclude that CTLA4-Ig (most likely in combination with other agents) may represent an important new modality for GVHD prevention.

Abatacept↗
PubMed1994

Simple bladder filling with a cough stress test compared with subtracted cystometry for the diagnosis of urinary incontinence.

OBJECTIVE: Our purpose was to compare the diagnostic efficacy of observing urine loss during simple bladder filling (without pressure measurement) and a cough stress test, with multichannel subtracted cystometry. STUDY DESIGN: The urodynamic records of 77 women complaining of urinary incontinence were reviewed. All women had undergone a full evaluation that included a standardized history and physical examination, urinalysis and urine culture, uroflowmetry with measurement of postvoid residual urine, a cough stress test performed during and after simple retrograde bladder filling, and multichannel subtracted cystometry. The results of simple bladder filling and the cough stress test were recorded as "urge incontinence," "stress incontinence,"mixed incontinence," or "incontinence not demonstrated." The subtracted cystometrogram was then performed, and the urodynamic diagnoses were recorded as "detrusor instability," "genuine stress incontinence," "mixed incontinence," or "incontinence not demonstrated." The records were reviewed, and the results of simple bladder filling with a cough stress test were compared with those obtained by subtracted multichannel provocative cystometry. RESULTS: With the subtracted multichannel cystometrogram used as the "gold standard" for diagnosis, the demonstration of "urge incontinence" during simple bladder filling had a sensitivity of 64% and a specificity of 86.8% for the demonstration of detrusor instability during cystometry, with a positive predictive value of 83.3% and a negative predictive value of 70.2%. The demonstration of "stress incontinence" during simple bladder filling had a sensitivity of 88.1% and a specificity of 77.1% for the demonstration of "genuine" stress incontinence during cystometry, with a positive predictive value of 82% and a negative predictive value of 84.4%. CONCLUSIONS: The demonstration of urge incontinence during simple bladder filling is a reliable predictor of detrusor instability, but its absence is less reliable in excluding detrusor overactivity as a cause of urinary incontinence. Similarly, the clinical demonstration of stress incontinence during simple bladder filling is predictive of the presence of "genuine" stress incontinence during subtracted multichannel provocative cystometry. The inability to demonstrate stress incontinence during simple bladder filling is highly correlated with the absence of "genuine" stress incontinence during complex urodynamic testing. Simple bladder filling is a reliable method of diagnosing urinary incontinence. In many cases it can replace complex urodynamic testing, particularly if the proposed treatment for the condition carries a low level of risk, and is helpful in selecting patients who need more extensive evaluation.

Cough↗
PubMed1994

The role of host T cell subsets in bone marrow rejection directed to isolated major histocompatibility complex class I versus class II differences of bm1 and bm12 mutant mice.

An expanded pool of unrelated donors (URD) is now being utilized for clinical allogeneic bone marrow transplantation. Because URD transplants can involve a mismatch at least at one genotypic MHC locus, we developed a C57BL/6 congenic mouse model to better understand graft rejection based exclusively on MHC class I or class II disparities. T cell-depleted (TCD) BM from class II-disparate mutant bm12 mice was transplanted into irradiated C57BL/6-Ly5.2 congenic hosts. These mice express a different allelic form of the Ly5 (CD45) marker than bm12 and thus permit definitive typing of reconstituted mice by flow cytometry. Peripheral blood typing indicated that host-mediated graft rejection was restricted to class II-reactive CD4+ cells since an anti-CD4 monoclonal antibody significantly inhibited rejection by enhancing the level of mean donor cell engraftment from 13% to 53%. The administration of anti-CD8 had no inhibitory effect on the ability of the recipient to reject the donor graft. Hematologic reconstitution studies revealed that there was a direct relationship between the level of donor cell engraftment and the extent of lymphoid, myeloid, and erythroid recovery. Mice that did not engraft had sustained reductions in in hematologic recovery. In other studies, TCD BM from bm1 mice mutated only in the MHC class I region was rejected by C57BL/6-Ly5.2 recipients. Anti-CD8 mAb infusion prevented the class I response resulting in an increase in the level of mean donor cell engraftment from 1% to 78%. Anti-CD4 alone had no effect. A CD4/CD8 T cell interaction could be important since the combination of anti-CD4 and anti-CD8 mAb resulted in significantly better donor engraftment than with the individual antibodies. Since the role of NK cells in these models has not been previously established and there is a reported association between NK cells and the rejection of BM cells that lack the expression of self-MHC antigens, we tested the role of NK cells. The elimination of NK cells using anti-NK mAb had no effect on graft rejection in either the bm1 or bm12 model. In addition to their value in exploring mechanisms of graft rejection, these models may prove useful for evaluating the efficacy of anti-BM rejection agents exclusively against class I- or class II-restricted disparities.

Alleles↗
PubMed1992

Promotion of murine marrow alloengraftment and hematopoietic recovery across the major histocompatibility barrier by administration of recombinant human interleukin-1 alpha.

Irradiated C57BL/6 (H-2b) recipients of T-cell-depleted (TCD) BALB/c (H-2d) bone marrow (BM) and recombinant interleukin-1 alpha (IL-1 alpha) (1 microgram/d) had a significantly (P less than or equal to .006) higher 100-day actuarial survival rate, accelerated hematopoietic recovery, and higher levels of alloengraftment than a group of transplanted control mice treated identically, but given phosphate-buffered saline (PBS). To elucidate the mechanisms involved with IL-1 alpha-induced promotion of alloengraftment and hematopoietic recovery, we performed sequential splenic FACS studies on transplanted mice and secondary transfer studies in syngeneic mice given IL-1 alpha or PBS. Splenic phenotyping showed that recipients of IL-1 alpha had a higher proportion of donor granulocytes (52% v 19%) as compared with PBS controls as early as 7 days after bone marrow transplantation (BMT). On day 11 post-BMT, recipients of IL-1 alpha had a more than fourfold increase in splenocyte number, which included a higher percentage (90% v 59%) of donor cells, especially donor granulocytes (52% vs 32%), and a sevenfold increase in donor T cells as compared with controls. Host T-cell numbers were not affected. Taken together, these data suggest that IL-1 alpha stimulated bipotential (myeloid and lymphoid) donor cell engraftment. In a syngeneic BMT system, administration of IL-1 alpha resulted in a higher incidence of survival when recipients were transplanted with BM cells, indicating that IL-1 alpha administration probably either expanded or potentiated engraftment of a committed progenitor cell pool. Secondary transfer experiments using marrow from IL-1 alpha-treated mice showed that the number of day 12 colony-forming unit-spleen (CFU-S) cells was unaltered compared with untreated control mice, suggesting that more primitive, albeit committed, hematopoietic progenitor cells were not affected. We also examined the potential additive effects of IL-1 alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) administered in combination (for 14 days). Mice receiving a suboptimal amount of IL-1 alpha along with GM-CSF had significantly higher levels of donor alloengraftment (92%) with superior hematopoietic recovery, as compared with mice receiving either IL-1 alpha (57%) or GM-CSF (18%) alone.

Animals↗
PubMed1991

Serving rural families of developmentally disabled children: a case management model.

Family-centered, community-based case management is a key feature of new federal legislation mandating educational and preschool services for all developmentally disabled children. Social work skills, including counseling, planning, coordination, and knowledge of family and community dynamics, are germane to this task. The goal of family-centered case management is the empowerment of parents as caretakers and planners for their children. Highly skilled case managers will be particularly needed in rural areas where families must deal with scarce resources and other environmental constraints. The authors describe a program employing master's-level social work case managers who serve rural Appalachian families with developmentally disabled children. Included is a case illustration that delineates both case management activities and the contextual elements important in working in an Appalachian rural community.

Child, Preschool↗
PubMed1990

Protective effects of KW-3635, a novel thromboxane A2 antagonist, in murine traumatic shock.

Pentobarbital anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension, increases in plasma cathepsin D (9.6-fold), free amino-nitrogen (4.0-fold), and myocardial depressant factor (5.2-fold) activities, and a survival time of 1.90 +/- 0.23 h. Following the induction of traumatic shock, plasma thromboxane B2 (TxB2) concentrations significantly increased from 3.12 +/- 0.68 to 6.78 +/- 0.27 pmol/ml. Treatment with the thromboxane receptor antagonist KW-3635 10 min post-trauma (2 mg/kg + 2 mg/kg per h, i.v.) prolonged survival time to 3.30 +/- 0.39 h (P less than 0.01) and attenuated the accumulation of cathepsin D compared to untreated trauma rats (6.6 +/- 1.1 and 13.6 +/- 1.3 U/ml, P less than 0.01), free amino-nitrogen (6.4 +/- 1.1 and 14.3 +/- 1.2 U/ml, P less than 0.01), and myocardial depressant factor (45 +/- 5 and 94 +/- 13 U/ml, P less than 0.02). However, KW-3635 did not prevent the increase in plasma TxB2 concentration, suggesting a lack of thromboxane synthetase inhibitory activity of this drug. The beneficial effects of thromboxane A2 (TxA2) antagonism in the present study are highly significant, and consistent with the concept that TxA2 is involved in the pathogenesis of traumatic shock.

Amines↗
PubMed1989

Evolution of late potential activity in the first six weeks after acute myocardial infarction.

The evolution of surface ventricular late potential activity was studied in 50 patients during the 6 weeks after first acute myocardial infarction (AMI). In 15 of 47 patients (32%) late potential activity appeared within 6 hours of the onset of major symptoms. Its prevalence overall remained approximately 30% at each recording time but with marked individual variability in appearance. Late potential activity was associated with late ventricular arrhythmias (greater than 24 hours after AMI) but not with early ventricular arrhythmias (less than 24 hours after AMI). Late ventricular arrhythmias or sudden death occurred only in the 6 patients with late potential activity (p less than 0.05). Early ventricular fibrillation (15 patients) occurred equally in the patients with and without late potential activity. Thus, late potential activity occurs at some stage in the first 6 weeks after AMI in 50% of patients, but its timing is variable. It is a sensitive but not specific predictor of late ventricular arrhythmias and sudden death, but not of early ventricular fibrillation.

Adult↗