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Kenneth A Newell

Publications and source records attributed to Kenneth A Newell.

17 recordsLinked to original sources
PubMed2006

How can we measure immunologic tolerance in humans?

Prevention and treatment of allograft rejection in organ transplant recipients relies primarily on non-antigen-specific immunosuppression, with all its associated potential hazards and costs. Currently, the status of the recipient immune response is measured by monitoring pharmacologic drug levels and clinical/pathologic evaluation of graft function. Development of reliable assays that can measure accurately the status of the immune response not only would help clinicians customize the prescription of immunosuppressive drugs in individual patients but also may allow their complete withdrawal in some patients with immunologic tolerance. Furthermore, these assays would facilitate the safe evaluation of novel tolerogenic regimens. Achieving this goal has proved to be very difficult because it requires both a more in-depth understanding of complex mechanisms of tolerance and also identification of transplant patients with acquired tolerance to an allograft that can be studied. This review discusses the current understanding of tolerance mechanisms and outlines the unique and specific challenges in development of tolerance/monitoring assays in the field of transplantation. In addition, several of the most promising candidate assays are discussed in detail.

Animals↗
PubMed2006

Tolerance assays: measuring the unknown.

Distinguishing transplant recipients who will benefit from a reduction in, or even the withdrawal of, immunosuppression from those who require intensive, lifelong immunosuppression will be dependent on developing strategies for immune monitoring. Currently, no assays have been shown to accurately predict the development or presence of donor-specific tolerance in humans after transplantation. In this overview we describe and discuss those assays that we believe may be useful for identifying tolerant transplant recipients. Validation of "tolerance" assays will be critical for the safe development of tolerance regimens in humans.

Biological Assay↗
PubMed2006

Immunosuppressive and trafficking properties of donor splenic and bone marrow dendritic cells.

BACKGROUND: Infusion of donor dendritic cells (DC) has been shown to prolong allograft survival in a number of models. However, many regimens that utilize donor DC do not consistently produced tolerance or long-term allograft survival. We hypothesized that one factor limiting the therapeutic effect of donor DC is their relative inability to traffic to recipient peripheral lymph nodes and inhibit the function of resident alloreactive T cells. METHODS: Donor strain DC isolated from the spleens or bone marrow of Flt3L-treated mice were transferred intravenously into recipients at the time of skin grafting. Where indicated, recipients were treated with an anti-CD40L antibody and CTLA4-Ig. RESULTS: Infusion of donor DC together with costimulatory blockade promoted donor-specific prolongation of skin allograft survival in mice. Perhaps due to their more immature phenotype, bone marrow DC trafficked more effectively to the spleen, bone marrow, and thymus and were associated with significantly longer allograft survival than were splenic DC. Neither population of DC trafficked well to peripheral lymph nodes. Consistent with our hypothesis, splenic but not lymph node T cells from DC-treated recipients displayed donor-specific hyporesponsiveness in vitro. CONCLUSION: These data suggest that one factor contributing to rejection following treatment with donor DC plus costimulation blockade is the persistence of donor-reactive T cells within the recipient's secondary lymphoid structures. Strategies to improve DC trafficking to these structures may enhance their therapeutic effect.

Animals↗
PubMed2006

Transplant tolerance: converging on a moving target.

Enthusiasm for tolerance induction has been tempered by the realization that it is more difficult to achieve clinically than was predicted by experimental models. Unlike the view that the immune response to an allograft is ordered and thus predictable, we view alloimmunity as highly plastic and molded by previous and ongoing experiences with allogeneic and environmental antigens. This implies that an individual's response to an allograft changes over time and that responses of seemingly similar individuals may vary greatly. This variability highlights the need to develop assays for monitoring the recipient immune response as well as individualized methods for therapeutic immune modulation.

Animals↗
PubMed2004

Intestinal cryptopatch formation in mice requires lymphotoxin alpha and the lymphotoxin beta receptor.

Interactions between lymphotoxin (LT)alpha(1)beta(2) on inducer cells and the lymphotoxin beta receptor (LTbetaR) on stromal cells initiate development of lymph nodes and Peyer's patches. In this study, we assessed the contributions of LTalpha and LTbetaR to the development of cryptopatches (CP), aggregates of T cell precursors in the mouse small intestine. Mice genetically deficient in LTalpha or LTbetaR lacked CP. Bone marrow from LTalpha-deficient mice was unable to initiate development of CP or isolated lymphoid follicles (ILF) after transfer to CD132-null mice lacking CP and ILF. However, LTalpha-deficient bone marrow-derived cells contributed to CP formed in CD132-null mice receiving a mixture of wild-type and LTalpha-deficient bone marrow cells. Transfer of wild-type bone marrow into irradiated LTalpha-deficient mice resulted in reconstitution of both CP and ILF. However, the LT-dependent formation of CP was distinguished from the LT-dependent formation of ILF and Peyer's patches by not requiring the presence of an intact NF-kappaB-inducing kinase gene. CP but not ILF were present in the small intestine from NF-kappaB-inducing kinase-deficient alymphoplasia mice, indicating that the alternate NF-kappaB activation pathway required for other types of LTbetaR-dependent lymphoid organogenesis is dispensable for CP development. In addition, we identified VCAM-1(+) cells within both CP and ILF that are candidates for the stromal cells involved in receiving LT-dependent signals from the hemopoietic precursors recruited to CP. These findings demonstrate that interactions between cells expressing LTalpha(1)beta(2) and LTbetaR are a shared feature in the development of all small intestinal lymphoid aggregates.

Animals↗
PubMed2003

Impaired NF-kappaB activation in T cells permits tolerance to primary heart allografts and to secondary donor skin grafts.

T-cell activation is essential for acute allograft rejection. However, the biochemical signaling pathways used by T cells mediating rejection have not been extensively investigated. In vitro, T-cell activation is associated with nuclear translocation of specific transcription factors that regulate expression of genes critical for T-cell function. Given the central role of NF-kappaB in T-cell activation In vitro, we examined its role in the acute rejection of skin and cardiac allografts using mice with defective NF-kappaB translocation in T cells due to the presence of a super repressor IkappaBalpha transgene. T-cell-intrinsic NF-kappaB activation was required for cardiac but not skin allograft rejection, suggesting differential T-cell priming by the two tissues. Strikingly, priming with heart allografts induced complete acceptance of subsequently transplanted donor skin grafts, indicating that impaired NF-kappaB activation in T cells facilitates the induction of donor-specific tolerance to highly immunogenic tissues. These data suggest the biochemical pathways necessary for allograft rejection vary, based on the antigen and the context in which it is presented, and that inhibition of T-cell-intrinsic NF-kappaB activation during allogeneic priming may represent a novel strategy whereby tolerance to transplanted organs can be achieved.

Abdomen↗
PubMed2003

Secondary lymphoid organs are important but not absolutely required for allograft responses.

The role of secondary lymphoid organs in adaptive immune responses following transplantation is controversial. To examine the requirement for peripheral lymphoid organs in mounting immune responses to transplantation antigens, lymphotoxin alpha-deficient (LTalpha-/-) and LTbeta-receptor-deficient (LTbetaR-/-) mice that lack lymph nodes and Peyer's patches were used as recipients of fully allogeneic heart and skin grafts. Splenectomized LTalpha-/- and LTbetaR-/- mice effectively rejected skin and cardiac allografts, although with delayed kinetics when compared with wild-type controls. In addition, initial skin allograft challenge in splenectomized LTbetaR-/- mice resulted in accelerated rejection of subsequent donor cardiac allografts when compared with heart rejection in nonsensitized controls. Thus, although peripheral lymphoid organs play an important role in allowing allograft responses to occur, they do not appear to be absolutely required for either acute allograft rejection, or T-cell priming. These results suggest that immunologic events capable of leading to allograft rejection can successfully occur at sites other than classical secondary lymphoid organs.

Animals↗
PubMed2003

Role of 4-1BB in allograft rejection mediated by CD8+ T cells.

Blockade of traditional costimulatory molecules fails to inhibit rejection in many models where CD8+ T cells are sufficient to mediate rejection. This observation demonstrates that in many settings CD8+ T cells are not dependent upon CD28 or CD154 signals to mediate rejection. 4-1BB (CD137) has been shown to be an important regulatory molecule for CD8+ T cells in a variety of nontransplant models. Here we show that blocking the 4-1BB pathway significantly inhibited rejection of intestinal allografts by CD8+ but not CD4+ T cells. This effect was associated with significantly decreased expression of the genes encoding TNFalpha and secondary lymphoid chemokine (SLC) within the spleens of recipient mice. Disruption of the 4-1BB pathway also impaired the priming of alloantigen-specific CD8+ T cells and the accumulation of recipient dendritic cells within the spleen. These data directly demonstrate an important role for 4-1BB in allograft rejection; particularly rejection mediated by CD8+ T cells. Our data suggest that in addition to providing a direct costimulatory signal to T cells, the 4-1BB pathway may regulate other important steps in the immune response such as the migration of T cells and dendritic cells.

Animals↗
PubMed2003

Long-term survival of intestinal allografts induced by costimulation blockade, busulfan and donor bone marrow infusion.

Tolerance-inducing strategies that infuse donor bone marrow cells in conjunction with costimulation blockade have not been applied to intestinal transplantation. Intestines from BALB/c mice were transplanted into C57BL/6 recipients treated with anti-CD40L mAb, CTLA4-Ig, donor bone marrow, and busulfan. The majority of mice transplanted after completion of this regimen developed hematopoietic macrochimerism, although the degree of chimerism varied widely between recipients, and experienced long-term allograft survival. T cells from these mice demonstrated donor-specific hyporesponsiveness in vitro. However, T cells from chimeric mice proliferated to donor alloantigen in vivo. Furthermore, chimeric mice bearing intestinal allografts were capable of rejecting subsequently placed donor-strain skin grafts. These data suggest that although long-term allograft survival occurs in the absence of acute or chronic rejection, recipient mice are not completely unresponsive to donor alloantigens. When intestinal transplantation was performed at the time of initial bone marrow infusion (initiation of the chimerism protocol), most recipients failed to develop chimerism and promptly rejected the intestinal allograft. Although this is the most effective protocol that we have tested using this stringent model of transplantation, our observations suggest that modifications will be necessary before it can be reliably applied to the transplantation of highly immunogeneic organs like the intestine.

Abatacept↗
PubMed2003

Conventional immunosuppression is compatible with costimulation blockade-based, mixed chimerism tolerance induction.

T-cell costimulatory blockade has emerged as an effective strategy to prevent allograft rejection in experimental models. We and others have reported that the beneficial effects of costimulation blockade can be negated when combined with certain immunosuppressants. The current study evaluates the compatibility of various immunosuppressive agents in a costimulation blockade-based, mixed chimerism tolerance protocol. The addition of conventional agents, including calcineurin inhibitors, did not interfere with tolerance induction. All mice developed multilineage macrochimerism and accepted donor allografts. Analysis of specific T-cell receptor utilization demonstrated selective deletion of donor-reactive T cells. Challenge with donor and third-party allografts confirmed donor-specific tolerance. Clinical introduction of costimulation blockade-based strategies will likely incorporate currently approved immunosuppressive agents. While it has been reported that certain conventional agents are detrimental to costimulation blockade-based strategies, our results suggest that these agents could safely be combined in clinical trials when used as part of a nonmyelosuppressive, mixed chimerism-based tolerance strategy.

Animals↗
PubMed2003

Simultaneous pancreas-kidney transplantation utilizing a common arterial conduit: early experience and potential applications.

Simultaneous pancreas-kidney transplantation has gained acceptance as a therapeutic modality for patients with end-stage renal disease secondary to diabetes mellitus. In some instances, performing the procedure as conventionally described with renal revascularization from the left iliac vessels and pancreatic arterial inflow from the right iliac vessels may be difficult or undesirable. We describe our experience with an alternate operative technique utilizing a single arterial conduit to vascularize both organs. We believe that this technique may be of use in certain patients undergoing simultaneous pancreas-kidney transplantation.

Anastomosis, Surgical↗
PubMed2002

Acute renal failure in endotoxemia is caused by TNF acting directly on TNF receptor-1 in kidney.

Bacterial endotoxin (LPS) is responsible for much of the widespread inflammatory response seen in sepsis, a condition often accompanied by acute renal failure (ARF). In this work we report that mice deficient in TNFR1 (TNFR1(-/-)) were resistant to LPS-induced renal failure. Compared with TNFR1(+/+) controls, TNFR1(-/-) mice had less apoptosis in renal cells and fewer neutrophils infiltrating the kidney following LPS administration, supporting these as mediators of ARF. TNFR1(+/+) kidneys transplanted into TNFR1(-/-) mice sustained severe ARF after LPS injection, which was not the case with TNFR1(-/-) kidneys transplanted into TNFR1(+/+) mice. Therefore, TNF is a key mediator of LPS-induced ARF, acting through its receptor TNFR1 in the kidney.

Acute Kidney Injury↗
PubMed2002

Signaling via LTbetaR on the lamina propria stromal cells of the gut is required for IgA production.

Peyer's patches (PPs) and/or mesenteric lymph nodes (MLNs) are thought to be essential for immunoglobulin A (IgA) production. We found that the severe IgA deficiency in lymphotoxin-deficient (LT(-/-)) mice could be fully reversed by reconstitution with LT-expressing bone marrow, despite the absence of both LNs and PPs. The number of IgA precursors from LT(-/-) mice was not reduced, and they were able to migrate into the lamina propria (LP) of wild-type mice but not of LTbetaR(-/-) mice. Consistently, lymphoid tissue chemokines and adhesion molecules were reduced within the LP of LTalpha(-/-) and LTbetaR(-/-) mice. IgA deficiency in LTalpha(-/-) mice was reversed by the transplantation of a segment of RAG-1 (recombination-activating gene 1) deficient intestine, which confirmed the dispensability of the MLNs and PPs and the sufficiency of the LT-mediated gut microenvironment for IgA production.

Adoptive Transfer↗
PubMed2002

The role of TNF receptor and TNF superfamily molecules in organ transplantation.

The rapid increase in the number of molecules demonstrated to regulate immune responses has provided new opportunities for manipulation of the recipient immune response to transplanted organs. Molecules belonging to the TNF receptors and TNF superfamily are increasingly recognized as playing a major role in the regulation of immune responses to tumor, viral, and autoantigens. The mechanisms by which these molecules regulate immune responses are diverse. TNF receptor-related molecules have been shown to control the development of secondary lymphoid organs, affect the activation and survival of T cells and antigen presenting cells, and alter cytokine and chemokine production. An increasing amount of data suggest that some TNFR superfamily members are particularly important for the function of CD8+ T cells. Based on our current understanding of these molecules it seems highly likely that strategies that target selected TNFR/TNF superfamily molecules will be useful for controlling or preventing the rejection of transplanted organs and tissues.

Humans↗
PubMed2002

Hand-assisted laparoscopic living-donor nephrectomy as an alternative to traditional laparoscopic living-donor nephrectomy.

The benefits of laparoscopic living-donor nephrectomy (LDN) are well described, while similar data on hand-assisted laparoscopic living-donor nephrectomy (HALDN) are lacking. We compare hand-assisted laparoscopic living-donor nephrectomy with open donor nephrectomy. One hundred consecutive hand-assisted laparoscopic living-donor nephrectomy (10/98-8/01) donor/recipient pairs were compared to 50 open donor nephrectomy pairs (8/97-1/00). Mean donor weights were similar (179.6 +/- 40.8 vs. 167.4 +/- 30.3 lb; p = NS), while donor age was greater among hand-assisted laparoscopic living-donor nephrectomy (38.2 +/- 9.5 vs. 31.2 +/- 7.8 year; p < 0.01). Right nephrectomies was fewer in hand-assisted laparoscopic living-donor nephrectomy [17/100 (17%) vs. 22/50 (44%); p < 0.05]. Operative time for hand-assisted laparoscopic living-donor nephrectomy (3.9 +/- 0.7 vs. 2.9 +/- 0.5 h; p < 0.01) was longer; however, return to diet (6.9 +/- 2.8 vs. 25.6 +/- 6.1 h; p < 0.01), narcotics requirement (17.9 +/- 6.3 vs. 56.3 +/- 6.4h; p < 0.01) and length of stay (51.7 +/- 22.2 vs. 129.6 +/- 65.7 h; p < 0.01) were less than open donor nephrectomy. Costs were similar ($11072 vs. 10840). Graft function and 1-week Cr of 1.4 +/- 0.9 vs. 1.6 +/- 1.1 g/dL (p = NS) were similar. With the introduction of HALDN, our laparoscopic living-donor nephrectomy program has increased by 20%. Thus, similar to traditional laparoscopic donor nephrectomy, hand-assisted laparoscopic living-donor nephrectomy provides advantages over open donor nephrectomy without increasing costs.

Activities of Daily Living↗
PubMedDate not supplied

Multidetector-row CT angiography for preoperative evaluation of potential laparoscopic renal donors: how accurate are we?

The purpose of this study was to evaluate multidetector-row computed tomography (MDCT) angiography in preoperative evaluation of renal donors for renal vascular abnormalities. Eighty-one patients underwent renal MDCT angiography and laparoscopic donor nephrectomy. MDCT angiographic findings were compared with surgical findings. The sensitivity and specificity of MDCT angiography for detection of accessory arteries, prehilar renal artery branching, and renal venous anomalies were 88% and 98%, 100% and 97%, and 100% and 97%, respectively. CT findings agreed with surgical findings for accessory renal arteries, prehilar renal artery branching, and renal venous anomalies in 94%, 93%, and 98% of patients, respectively.

Adult↗