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Multiparametric Quantitative Ultrasound Imaging in Assessment of Chronic Kidney Disease

Gao, Jing; Perlman, Alan; Kalache, Safa; Berman, Nathaniel; Seshan, Surya; Salvatore, Steven; Smith, Lindsey; Wehrli, Natasha; Waldron, Levi; Kodali, Hanish; Chevalier, James
OBJECTIVES/OBJECTIVE:To evaluate the value of multiparametric quantitative ultrasound imaging in assessing chronic kidney disease (CKD) using kidney biopsy pathologic findings as reference standards. METHODS:using receiver operating characteristic curve analysis. RESULTS:. Moderate to good correlations were found for PSV, EDV, and pixel intensity with pathologic scores and estimated GFR. CONCLUSIONS:The PSV, EDV, and pixel intensity are valuable in determining moderate to severe CKD. The value of shear wave velocity in assessing CKD needs further investigation.
PMID: 28407281
ISSN: 1550-9613
CID: 2970212

Effects of preexisting autoimmunity on heart graft prolongation after donor-specific transfusion and anti-CD154

Kalache, Safa; Lakhani, Parth; Heeger, Peter S
BACKGROUND:Alloreactive memory T cells prevent costimulatory blockade-induced heart graft survival in mice, but whether and how preexisting autoreactive T cells affect solid-organ transplants under these conditions is unknown. METHODS:We tested the impact of preexisting cardiac myosin (CM)-specific immunity on murine heart transplant recipients treated with donor-specific transfusion (DST) plus anti-CD154 monoclonal antibody MR1. RESULTS:Preimmunization with CM but not control ovalbumin abrogated the graft prolonging effects of DST/MR1, whether administered 2 weeks or more than 6 weeks before transplantation. Adoptive transfer of spleen cells from CM-immunized mice into naïve recipients had similar effects. CM-specific immunity did not cross-react with donor antigens and preimmunization with CM had no impact on the survival or histology of DST/MR1-treated syngeneic heart grafts, the latter indicating that persistent autoimmunity is insufficient to cause rejection in the context of costimulatory blockade. We observed that the CM preimmunized mice produced higher frequencies of donor-reactive T cells with higher ratios of CD8/CD4Foxp3 cells, suggesting that the autoreactive memory T cells provide help for activation of alloreactive T cells despite the costimulatory blockade. CONCLUSIONS:These mechanistic insights linking autoimmunity and alloimmunity in a model of murine heart transplantation have clinical relevance to the known association between autoimmunity and an elevated risk of acute and chronic heart transplant injury in humans.
PMID: 24056628
ISSN: 1534-6080
CID: 2970202

Anticardiac myosin immunity and chronic allograft vasculopathy in heart transplant recipients

Kalache, Safa; Dinavahi, Rajani; Pinney, Sean; Mehrotra, Anita; Cunningham, Madeleine W; Heeger, Peter S
Chronic allograft vasculopathy (CAV) contributes to heart transplant failure, yet its pathogenesis is incompletely understood. Although cellular and humoral alloimmunity are accepted pathogenic mediators, animal models suggest that T cells and Abs reactive to graft-expressed autoantigens, including cardiac myosin (CM), could participate. To test the relationship between CAV and anti-CM autoimmunity in humans, we performed a cross-sectional study of 72 heart transplant recipients: 40 with CAV and 32 without. Sera from 65% of patients with CAV contained anti-CM Abs, whereas <10% contained Abs to other autoantigens (p < 0.05), and only 18% contained anti-HLA Abs (p < 0.05 versus anti-CM). In contrast, 13% of sera from patients without CAV contained anti-CM Abs (p < 0.05; odds ratio [OR], associating CAV with anti-CM Ab = 13, 95% confidence interval [CI] 3.79-44.6). Multivariable analysis confirmed the association to be independent of time posttransplant and the presence of anti-HLA Abs (OR = 28, 95% CI 5.77-133.56). PBMCs from patients with CAV responded more frequently to, and to a broader array of, CM-derived peptides than those without CAV (p = 0.01). Detection of either CM-peptide-reactive T cells or anti-CM Abs was highly and independently indicative of CAV (OR = 45, 95% CI 4.04-500.69). Our data suggest detection of anti-CM immunity could be used as a biomarker for outcome in heart transplantation recipients and support the need for further studies to assess whether anti-CM immunity is a pathogenic mediator of CAV.
PMID: 21677143
ISSN: 1550-6606
CID: 2970192

Induction of Human Regulatory T Cells by a Human MHC-Class II Derived Peptide. [Meeting Abstract]

Luan, Yi; Zang, Weiping; Kalache, Safa; Murphy, Barbara
ISSN: 1600-6135
CID: 2970242

Inhibition of the alloimmune response through the generation of regulatory T cells by a MHC class II-derived peptide

Zang, Weiping; Lin, Marvin; Kalache, Safa; Zhang, Nan; Krüger, Bernd; Waaga-Gasser, Ana Maria; Grimm, Martin; Hancock, Wayne; Heeger, Peter; Schröppel, Bernd; Murphy, Barbara
We have previously shown that HLA-DQA1, a peptide derived from a highly conserved region of MHC class II, prevents alloreactive T cell priming and effector function in vivo, although underlying mechanisms are obscure. In this study, we demonstrate that 28% of mice treated with HLA-DQA1 combined with low-dose rapamycin achieved permanent engraftment of fully MHC-disparate islet allografts and significantly prolonged survival in the remaining animals (log rank, p < 0.001). Immunohistologic examination of the grafts from HLA-DQA1/rapamycin-treated animals revealed up-regulated expression of TGF-ss and FoxP3. In vivo administration of blocking anti-TGF-ss or depleting anti-CD25 mAb augmented T cell alloimmunity and prevented the long-term engraft induced by HLA-DQA1. In vitro experiments further showed that HLA-DQA1 induced differentiation of CD4(+) T cells into CD4(+)CD25(+)FoxP3(+) regulatory T cells. Together, these data provide the first demonstration that HLA-DQA1, a MHC class II-derived peptide, can prolong allograft survival via a TGF-beta and regulatory T cell-dependent mechanisms.
PMID: 19017939
ISSN: 1550-6606
CID: 2970182

The association of Hashimoto disease and Congo red negative amyloidosis [Case Report]

Chaiban, Joumana T; Kalache, Safa M; Abu Alfa, Ali K; Shabb, Nina S; Salti, Ibrahim S
Systemic amyloidosis which is characterized by extracellular deposition of monoclonal immunoglobulin light chains in various organs may be difficult to diagnose at an early stage, especially when the Congo red stain is negative. We describe herein a case of Congo red negative primary amyloidosis associated with Hashimoto thyroiditis. The patient presented with multiple organ involvement suggestive of amyloidosis including heart failure, renal failure, and macroglossia. Serum and urine immunofixation studies were positive for monoclonal chains. Even though a biopsy taken from the enlarged tongue of the patient was negative when stained with Congo red, electron microscopy showed ultrastructural features of amyloid deposition. In conclusion, we are reporting a rare case of primary amyloidosis with a negative Congo red stain associated with Hashimoto thyroiditis.
PMID: 18794630
ISSN: 0002-9629
CID: 2969082

Inhibition of the alloimmune response through the generation of regulatory T cells by an MHC class II derived peptide [Meeting Abstract]

Zang, Weiping; Kalache, Safa; Zhang, Nan; Krueger, Bernd; Waaga-Gasser, Ana Maria; Hancock, Wayne; Heeger, Peter; Schroeppel, Bernd; Murphy, Barbara
ISSN: 1600-6135
CID: 2970232

Treatment with an MHC class H-derived peptide prolongs vascularized heart allograft survival. [Meeting Abstract]

Zang, Weiping; Kalache, Safa; Wagga-Gasser, Ana-Maria; Grimm, Martin; Schroppel, Bernd; Murphy, Barbara
ISSN: 1600-6135
CID: 2970222

MHC Class II-mediated apoptosis by a nonpolymorphic MHC Class II peptide proceeds by activation of protein kinase C

Zang, Weiping; Kalache, Safa; Lin, Marvin; Schroppel, Bernd; Murphy, Barbara
It was demonstrated previously that a peptide derived from a conserved region of MHC class II, HLA-DQA1, inhibits proliferation of allogeneic T cells in vitro. Administration of HLA-DQA1 in conjunction with allogeneic cells at the time of priming or at the time of rechallenge prevented the development of the delayed type hypersensitivity response in vivo. The immunomodulatory effects of HLA-DQA1 were associated with the induction of apoptosis in B cells, macrophages, and dendritic cells via a caspase-independent pathway. This study investigated the binding site and mechanism that mediates cell death induced by HLA-DQA1. It was demonstrated that HLA-DQA1 binds to MHC class II on the cell surface, causing MHC class II signaling, initiation of protein kinase C signaling, and mitochondrial membrane depolarization with resultant apoptosis. The data indicate that HLA-DQA1 binds to MHC class II outside the groove, in a manner similar to superantigen. These results suggest that HLA-DQA1 is a novel immunotherapy that may provide an effective means of targeting professional antigen-presenting cells, in particular B cells.
PMID: 16221866
ISSN: 1046-6673
CID: 2970172