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N L Reinsmoen

Publications and source records attributed to N L Reinsmoen.

At least 19 recordsLinked to original sources
PubMed2007

Genetic regulation of rejection and survival following human lung transplantation by the innate immune receptor CD14.

We have developed the hypothesis that genetic polymorphisms which alter the expression or function of innate immune receptors contribute to the marked interindividual differences in the onset and severity of lung transplant rejection. In this analysis, we considered the effects of a common promotor polymorphism of the lipopolysaccharide receptor CD14 associated with increased transcriptional activity upon the development of posttransplant rejection and graft survival. Genotyping was performed in 226 lung transplant recipients well characterized with regards to clinical outcomes. An earlier onset of acute rejection, bronchiolitis obliterans syndrome (BOS) and worse posttransplant graft survival due to greater BOS related deaths was evident in patients with the CD14 -159 TT genotype (TT). The adverse effect upon graft survival of the TT genotype remained significant in a multivariate Cox model (Hazard Ratio 1.65, 95% CI, 1.03-2.64, p-value = 0.04) after adjusting for other important covariates. Furthermore, TT patients have significantly greater sCD14, TNF-alpha and IFN-gamma in the peripheral blood implying a heightened state of innate immune activation drives the development of increased post-transplant rejection. Inhibition of innate immune activation through CD14 represents a novel and potentially important therapeutic target to prevent post-transplant rejection and improve outcomes after human lung transplantation.

Adult↗
PubMed2006

The effect of natural killer cell killer Ig-like receptor alloreactivity on the outcome of bone marrow stem cell transplantation for severe combined immunodeficiency (SCID).

Natural killer (NK) cell alloreactions against recipient cells in the setting of bone marrow transplantation have been associated with decreased rates of graft-versus-host disease (GVHD) and improved survival in transplant recipients with myeloid leukemia. These alloreactions are predicted by the absence of recipient HLA class I ligands for donor inhibitory killer Ig-like receptors (KIR). We hypothesized that donor NK cell alloreactions against recipient cells may affect the development of T and B-cell functions and incidence of GVHD in infants with severe combined immunodeficiency (SCID). Of the 156 patients with SCID who had received related bone marrow transplants without pretransplant chemotherapy or posttransplant GVHD prophylaxis, 137 patient-donor pairs were evaluated for the absence of recipient HLA class I ligands for donor inhibitory KIR. Analysis showed that the absence of a KIR ligand had no effect on the incidence or severity of GVHD (RR [corrected] = 0.95, p = 0.84), development of T-cell function (RR [corrected] = 1.05, p = 0.69), production of IgA (p = 0.46) or IgM (p = 0.33), or on 5-year survival (RR [corrected] = 1.21, p = 0.10). Further, in patients possessing native NK cells, the absence of KIR ligands in donors for recipient-inhibitory KIR did not alter transplantation outcomes. This study suggests that inhibitory KIR/HLA interactions do not play a significant role in bone marrow transplantation for SCID.

Bone Marrow Transplantation↗
PubMed2002

Cellular methods used to evaluate the immune response in transplantation.

Cellular assays have been developed to test for various effector, cytotoxic, and regulatory functions of T cells and have been used throughout the history of clinical transplantation to assess the immune profile of solid organ and marrow recipients. One goal of these cellular studies has been to determine if posttransplant changes in the donor antigen-specific cellular response could predict good and poor graft outcome, thereby allowing for individualization of immunosuppression. This review outlines the use of established and newly developed cellular assays to assess the dynamic processes of the posttransplant immune response and to provide insights into the mechanisms involved and potential points for intervention.

Enzyme-Linked Immunosorbent Assay↗
PubMed2000

Influence of panel-reactive antibodies on posttransplant outcomes in lung transplant recipients.

BACKGROUND: Panel-reactive antibody (PRA) is used to estimate the degree of humoral sensitization in the recipient before transplantation. Although pretransplant sensitization is associated with increased complications in other solid organ transplant recipients, less is known about the outcome of sensitized lung transplant recipients. Therefore, we sought to determine the impact of elevated pretransplant PRA on clinical outcomes after lung transplantation. METHODS: The records of the first 200 lung transplant operations performed at Duke University Medical Center were reviewed. The outcomes of sensitized patients, PRA greater than 10% before transplantation (n = 18), were compared with the outcomes of nonsensitized patients. RESULTS: Sensitized patients experienced a significantly greater number of median ventilator days posttransplant (9 +/- 8) as compared with nonsensitized recipients (1 +/- 11; p = 0.0008). There were no significant differences between the number of episodes of acute rejection; however, there was a significantly increased incidence of bronchiolitis obliterans syndrome occurring in untreated sensitized recipients (56%) versus nonsensitized (23%; p = 0.044). In addition, there was a trend towards decreased survival in the sensitized recipients, with a 2-year survival of 58% in sensitized recipients as compared with 73% in the nonsensitized patients (p = 0.31). CONCLUSIONS: Sensitized lung transplant recipients experience more acute and chronic complications after transplantation. These patients probably warrant alternative management strategies.

Adolescent↗
PubMed1999

Evaluation of pre- and posttransplant donor-specific transfusion/cyclosporine A in non-HLA identical living donor kidney transplant recipients. Cooperative Clinical Trials in Transplantation Research Group.

BACKGROUND: The beneficial effects of donor specific transfusion (DST) have become controversial in the cyclosporine era. This study was performed to evaluate the potential benefits of a new protocol for administering DSTs in the perioperative period. METHODS: Non-HLA identical living donor kidney transplant recipients were randomized prospectively to control or to receive a DST 24 hr before transplant and 7-10 days posttransplant. All patients received similar immunosuppression according to protocol. RESULTS: The protocol had 212 evaluable patients (115 transfused and 97 control). There were no differences in 1- and 2-year graft and patient survival, causes of graft failure, incidence and types of infection, repeat hospitalization, or the ability to withdraw steroids. Immunological hyporesponsiveness (by mixed lymphocyte culture) occurred more frequently in transfused patients (18%) than controls (3%) (P = 0.04). Blood stored for > or =3 days was associated with fewer early rejections than blood stored < or =2 days. Overall, class II antigen mismatches were associated with more rejection episodes than class I antigen mismatches. However, transfused patients, but not control patients, with more class I antigen mismatches were more likely to have rejections. CONCLUSIONS: Administration of DSTs by the method described had no practical influence on patient or graft survival for up to 2 years. However, donor-specific hyporesponsiveness was more common in transfused patients (18 vs. 3%). Longer follow-up will be needed to determine whether DST will be associated with long-term benefit.

Blood Preservation↗
PubMed1999

Impact of transfusions and acute rejection on posttransplantation donor antigen-specific responses in two study populations. Cooperative Clinical Trial in Transplantation Research Group.

BACKGROUND: We participated in a protocol supported by the National Institutes of Allergy and Infectious Disease, Cooperative Clinical Trial in Transplantation (CCTT), which was designed to investigate the effect of peritransplant donor-specific transfusion in non-HLA-identical living donor kidney recipients. METHODS: We determined the donor antigen-specific responses at 1 year after transplantation for the 79 CCTT donor-recipient combinations in this study. A lower rate of donor antigen-specific hyporeactivity was seen in the CCTT recipients (6 of 79=8%) versus our recipients at the University of Minnesota who underwent transplantation in the same period (9 of 55=16%, P=0.16) and versus our combined historical data (33 of 131=25%, P=0.002). Therefore, we studied the differences in the two recipient populations to determine why hyporeactivity was lower in the CCTT group than at our center. RESULTS: Significant differences were seen in the acute rejection rates and the frequency of pretransplantation random transfusion. Overall and early (<3 month) acute rejection rates were higher in CCTT versus Minnesota recipients (overall: 51% vs. 20%, P=0.001) (early: 43% vs. 16%, P=0.001). The frequency of pretransplantation random transfusion was 40% for CCTT recipients (34%) versus 80% for Minnesota recipients (75%) (P=0.0004). CONCLUSIONS: These results provide provocative, although not conclusive, evidence for the importance of pretransplantation transfusion and acute rejection episodes in the development of donor antigen-specific hyporeactivity. Pre-, peri-, and posttransplantation clinical events undoubtedly have an impact on posttransplantation immune parameters.

Azathioprine↗
PubMed1999

Peripheral blood allogeneic microchimerism in lung and cardiac allograft recipients.

We have been investigating two parameters, donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism, to determine whether these parameters will predict a chronic rejection-free state and which recipients may be candidates for steroid withdrawal. We have identified donor antigen-specific hyporeactivity for 33% (16/48) of lung and 23% (11/47) of heart recipients. For both organ groups, the hyporeactive subgroup experienced a lower incidence of chronic rejection. The probability of donor antigen-specific hyporeactivity predicting a chronic rejection-free state is 100% for lung and 91% for heart recipients. We have identified peripheral blood allogeneic microchimerism for 77% (20/26) of lung and 36% (9/25) of heart recipients tested at 12-18 months posttransplant. Donor antigen-specific hyporeactivity correlates with a critical level of donor cells in lung recipients; the probability of high peripheral blood allogeneic microchimerism levels predicting a chronic rejection-free state in lung recipients is 100%. The results in heart recipients are not as clear with a short-, but not long-term, trend of higher chimerism levels correlating with the development of donor antigen-specific hyporeactivity. These results illustrate the usefulness of immmune parameters to predict long-term graft outcome in an organ-specific manner.

Bronchiolitis Obliterans↗
PubMed1997

Pretransplant exposure to donor HLA-DR antigen in random transfusion units and the development of donor antigen-specific hyporeactivity.

Our previous studies have shown that the in vitro assay of donor antigen-specific hyporeactivity is a useful marker for identifying solid organ transplant recipients (kidney, lung and heart) at low risk for immunologic complications (i.e., late acute rejection episodes and chronic rejection). Donor antigen-specific hyporeactivity is defined as a significantly decreased post- vs. pretransplant proliferative response to donor antigens while response to third-party controls remains unchanged. We analyzed whether exposure to the same HLA-DR antigen pretransplant via random blood transfusion and posttransplant via the transplanted organ influenced the development of hyporeactivity. Thirty previously nontransfused recipients, each receiving two 150 ml pretransplant random blood transfusions, were assessed for hyporeactivity at 1 year posttransplant. Of the 12 recipients with pretransplant exposure to kidney HLA-DR via transfusions, 6 (50%) developed hyporesponsiveness; in contrast, of the 18 recipients who were not preexposed, only 3 (15%) exhibited this form of immunomodulation. Of interest, 2 of the 3 hyporesponsive recipients who were not preexposed, received units containing HLA-DR antigens previously shown to share crossreactive epitopes with the kidney HLA-DR. In conclusion, these results suggest a increased incidence in the development of hyporeactivity in patients receiving pretransplant transfusions which share an HLA-DR antigen with the transplanted kidney.

Blood Transfusion↗
PubMed1996

Sequential measurement of peripheral blood allogeneic microchimerism levels and association with pulmonary function.

We have shown in lung recipients that high levels of peripheral blood allogeneic microchimerism at 12 to 18 months posttransplant correlated with donor antigen-specific hyporeactivity (i.e., decreased proliferative response to donor antigen in MLC while response to 3rd-party cells remains unchanged); both parameters correlated with an obliterative bronchiolitis (OB)-free state. We have expanded these studies to determine any association of sequential microchimerism levels with concomitant clinical events. In this preliminary study of 7 lung recipients, we used limiting-dilution PCR to quantify peripheral blood microchimerism at serial timepoints ranging from 3 to >48 months posttransplant. These levels were compared with a variety of immunologic and clinical parameters: acute rejection, CMV infection, OB, donor antigen-specific hyporeactivity, and pulmonary function. Pulmonary function was measured per the International Society of Heart and Lung Transplantation: "current FEV1/ baseline FEV1" (FEV1: forced expiratory volume in 1 second). Of the clinical parameters, the association between microchimerism and pulmonary function was the most striking. We observed dynamic patterns of peripheral microchimerism, which reflected the general rise and fall of FEV1. In all 7 recipients, chimerism and FEV1 were high very early posttransplant, then dropped at various rates and to various degrees. After its initial decline, microchimerism increased with FEV1 for the 1 hyporesponsive recipient; for the other 6 recipients, both values declined. These results illustrate, for the first time, that the fluctuation of peripheral blood microchimerism levels is associated with the recipient's clinical condition.

Blood Grouping and Crossmatching↗
PubMed1995

Organ-specific patterns of donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism in lung, kidney, and liver transplant recipients.

Although their relative importance and interaction are unclear, donor antigen(Ag)*-specific hyporeactivity and allogeneic microchimerism have been associated with improved long-term graft outcome and a lower incidence of chronic rejection in solid organ transplant recipients. We have postulated that a critical level of donor antigen, for a critical time period, is necessary to develop and maintain donor antigen-specific hyporeactivity; both the level and the time may differ by organ transplanted. In our current study, we tested donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism in liver and kidney recipients and compared these values with our previous findings in lung recipients. We tested 25 liver recipients at 12 to 29 months posttransplant: 10 (40%) had developed donor antigen-specific hyporeactivity; 5 (20%), peripheral blood allogeneic microchimerism. For all but 1 of the chimeric and hyporeactive recipients, the level of donor cells was very low (< 1:20,000). Five hyporeactive recipients and all 15 donor antigen-responsive recipients did not have detectable levels of peripheral blood microchimerism. No chronic rejection has developed in any of these recipients to date--however, a lower incidence of acute rejection was observed for those recipients with donor antigen-specific hyporeactivity (30% versus 60% without) or with peripheral blood allogeneic microchimerism (20% versus 55% without) (P = ns). These results differ from our previous findings in 19 lung recipients: at 12 to 18 months posttransplant, 35% of them had developed donor antigen-specific hyporeactivity; 47%, peripheral blood allogeneic microchimerism. All donor antigen-specific hyporeactivity recipients as well as some donor antigen-responsive recipients had peripheral blood allogeneic microchimerism. We expanded our current study to include 26 recipients and a quantitative estimate of the level of allogeneic microchimerism. We observed that the hyporesponsive recipients tended to have higher levels of donor cells in their peripheral blood (> 1:6,000) than did the responsive recipients. We previously reported that 22% of kidney recipients had developed donor antigen-specific hyporeactivity at 12 to 18 months posttransplant. In our current study of 33 kidney recipients, we observed peripheral blood allogeneic microchimerism in 7 (21%) at 12 to 18 months posttransplant. The level of donor cells was very low (approximately 1:75,000), with no correlation between donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism at the time point tested. These studies emphasize the organ-specific nature of the development of donor antigen-specific hyporeactivity and the persistence of peripheral blood allogeneic microchimerism. Donor antigen-specific hyporeactivity correlates with very low levels of donor cells in liver recipients, while a higher critical level of donor cells is important in lung recipients. Additional sequential early posttransplant studies are necessary to further define the possible interrelationship between donor antigen and the development and maintenance of donor antigen-specific hyporeactivity.

Antigen Presentation↗
PubMed1995

Correction of proliferative responses in purine nucleoside phosphorylase (PNP)-deficient T lymphocytes by retroviral-mediated PNP gene transfer and expression.

Purine nucleoside phosphorylase (PNP; EC 2.4.2.1) deficiency is associated with a fatal T cell immunodeficiency in children, a candidate condition for gene therapy by introduction of functional PNP sequences into either T lymphocytes or more primitive progenitor cells in the bone marrow. To test the effectiveness of PNP gene transfer in T lymphocytes, a retroviral vector (LmPSN-2) was designed and constructed to express the murine PNP cDNA under transcriptional regulation of the Moloney murine leukemia virus long terminal repeat. LmPSN-2 was first used to mediate gene transfer and expression of electrophoretically distinct murine PNP in normal (PNP-positive) human PBL. Peripheral blood leukocytes were then obtained from a PNP deficient patient and characterized phenotypically. Despite their paucity and general mitogenic unresponsiveness, T lymphocytes from this patient were successfully grown in culture by using anti-CD3 with rIL-2 and then transduced with LmPSN-2. Elevated PNP enzyme activity was observed in the transduced cell population. Mitogenic and allogeneic responses, normally depressed in PNP-deficient patients' cells, were partially corrected in the transduced cell population relative to nontransduced cells. These results suggest the possibility of effecting improved immunologic function in PNP-deficient T lymphoid cells by retroviral-mediated gene transfer as therapy for PNP deficiency.

3T3 Cells↗
PubMed1995

Beyond hyperacute rejection. Accelerated rejection in a discordant xenograft model by adoptive transfer of specific cell subsets.

If hyperacute rejection is prevented in the guineapig (GP)-to-Lewis rat (Lew) cardiac xenograft (CXg) model, an accelerated rejection involving cellular infiltration occurs in 3 to 4 days. In previous work using an adoptive transfer model, we found that this accelerated rejection was facilitated by either sensitized splenocytes or sensitized serum. In the current study, in an attempt to determine which splenocyte subset(s) facilitated this process, sensitized splenocytes, with or without subset depletion were injected, into complement- and natural antibody-depleted Lew recipients of GP CXgs. Graft survival was 4.18 +/- 0.75 days with no injection (n = 11), 4.13 +/- 0.99 days with naive splenocytes (n = 8), 1.80 +/- 0.45 days with sensitized splenocytes (n = 5), 2.67 +/- 1.03 days with CD4(W3/25+) depletion of the sensitized splenocytes (n = 6), 3.13 +/- 0.84 days with CD8(OX8+) cell depletion (n = 8), 4.70 +/- 0.68 days with macrophage depletion (n = 10), and 4.22 +/- 0.41 days with B cell depletion (n = 9). Cellular infiltrates, hemorrhage, myocyte necrosis, and endothelial deposition of IgG, IgM, and fibrin were seen in rejected grafts. In most groups, infiltrating cells consisted of CD4 (W3/25+), CD8 (OX8+), IL2R+ cells, macrophages, and natural killer (NK) cells. However, in the macrophages-depleted group, activated (ED2+) macrophages and NK cells were significantly reduced. Total IgM, anti-GP IgM, and anti-GP IgG rebounded in all groups over several days but were not consistent at the time of rejection. Lewis rats rejecting GP CXgs early had lower final titers than those rejecting later. Total IgG titers rebounded to baseline by posttransplant day 1 and were therefore similar in all groups at the time of rejection. These findings suggest that this accelerated rejection requires interaction between macrophages and B cells, since depletion of either significantly alters the rejection tempo. A possible explanation is that xenoreactive IgG antibodies, synthesized by sensitized B cells, bind their target antigens--but also bind sensitized macrophages through their Fc region, thus causing rejection by antibody-dependent cell-mediated cytotoxicity.

Acute Disease↗
PubMed1995

Correlation of donor antigen-specific hyporeactivity with allogeneic microchimerism in kidney and lung recipients.

Our previous studies indicate donor antigen-specific hyporeactivity is a useful marker for identifying solid organ transplant recipients at low risk for immunological complications; the hyporeactive subgroup experiences a lower incidence of chronic rejection. One purpose of the current study was to determine whether hyporeactivity could be identified in pediatric kidney recipients and whether it correlated with improved graft outcome. Of 18 pediatric kidney recipients tested, 6 (33%) had developed donor antigen-specific hyporeactivity. All 18 experienced good graft outcome. Second, we determined whether donor antigen-specific hyporeactivity correlates with peripheral blood microchimerism and outcome in adult kidney recipients. Our previous studies of lung recipients demonstrated development of obliterative bronchiolitis in recipients with microchimerism who remain responsive, but not in recipients who had become hyporesponsive to donor antigen. Preliminary results in our current study of 23 adult kidney recipients indicate microchimerism for 6 (26%): 4 hyporesponsive and 2 responsive to donor antigen. Microchimerism was not detected for 17 recipients: 6 hyporesponsive and 11 responsive to donor antigen. One hyporesponsive/chimeric patient and 4 recipients negative for both parameters have been diagnosed with biopsy-proven chronic rejection. In summary, both hyporeactivity and chimerism are found at a higher frequency in lung than kidney recipients. Unlike lung recipients, not all hyporesponsive kidney recipients had peripheral blood chimerism. Additional numbers are needed to determine if microchimerism correlates with donor antigen-specific hyporeactivity or graft outcome.

Adult↗
PubMed1995

A description of a new DR allele, DRB1*1113.

We have discovered a previously unpublished HLA-DRB1 allele, observed in a patient (SB), his mother, and one sibling. The undefined allele gave sporadic positive reactions with sera in the DR52-associated group. SSOPH analysis utilizing both generic and group specific primers and probes also gave ambiguous results. SB typed clearly as a DRB1*0301 (paternal allele) but the DNA from SB also bound probes specific for DRB1*14 and DRB1*11. Sequencing revealed that the undefined allele was similar to a DRB1*14 allele with a segment of sequence found in DRB1*11 alleles. The patient was MLC reactive with donors who express DRB1*0301, *1401 and *0301, *11 and was nonreactive solely to DRB1*0301 (Dw3) homozygous typing cells.

Alleles↗
PubMed1995

Allogeneic microchimerism and donor antigen-specific hyporeactivity in lung transplant recipients.

The identification of peripheral donor cells in solid organ transplant recipients has led to speculation as to the tolerogenic role of circulating donor cells. Also being debated is the possible significance of persistent donor alloantigen-presenting cells in inducing and maintaining an alloantigen-specific unresponsive state. Previously, we showed that donor antigen-specific hyporeactivity is a useful marker for identifying kidney, lung, or heart recipients at low risk for immunologic complications; we found donor antigen-specific hyporeactivity in 25% of kidney, 35% of lung, and 22% of heart recipients. All 3 hyporeactive subgroups experienced fewer late (> 3 months) rejection episodes and a lower incidence of chronic rejection. The purpose of the current study was to determine whether peripheral blood microchimerism correlates with the development of donor antigen-specific hyporeactivity and affects clinical outcome. We correlated the detection of microchimerism with in vitro proliferative response to donor antigen in 19 lung recipients who were > or = 12 months posttransplant. Allogeneic peripheral blood microchimerism was studied with a PCR-based limiting detection assay using HLA-DR sequence-specific primers. We detected microchimerism in 47% (9 of 19) of the lung recipients tested. All recipients who were donor antigen-specific hyporesponsive had microchimerism, and all recipients without detectable microchimerism were responsive to donor antigen. However, not all recipients with microchimerism developed donor antigen-specific hyporeactivity. Further, none of the hyporesponsive recipients has been diagnosed with obliterative bronchiolitis (OB). In contrast, 2 of the 4 with microchimerism who were responsive to donor antigen have been diagnosed with OB, as have 5 of the 10 who were negative for both hyporeactivity and microchimerism. Thus, long-term graft outcome may correlate more closely with donor antigen-specific hyporeactivity than with microchimerism.

Antigen-Presenting Cells↗