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Tolkoff-Rubin, Nina

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Tolkoff-Rubin

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Nina

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Tolkoff-Rubin, Nina
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    HLA-Mismatched Renal Transplantation without Maintenance Immunosuppression
    (New England Journal of Medicine (NEJM/MMS), 2008) Kawai, Tatsuo; Cosimi, A.; Spitzer, Thomas; Tolkoff-Rubin, Nina; Suthanthiran, Manikkam; Saidman, Susan; Shaffer, Juanita; Preffer, Frederic; Ding, Ruchuang; Sharma, Vijay; Fishman, Jay; Dey, Bimalangshu; Ko, Dicken; Hertl, Martin; Goes, Nelson B.; Wong, Waichi; Williams, Winfred; Colvin, Robert; Sykes, Megan; Sachs, David
    Five patients with end-stage renal disease received combined bone marrow and kidney transplants from HLA single-haplotype mismatched living related donors, with the use of a nonmyeloablative preparative regimen. Transient chimerism and reversible capillary leak syndrome developed in all recipients. Irreversible humoral rejection occurred in one patient. In the other four recipients, it was possible to discontinue all immunosuppressive therapy 9 to 14 months after the transplantation, and renal function has remained stable for 2.0 to 5.3 years since transplantation. The T cells from these four recipients, tested in vitro, showed donor-specific unresponsiveness and in specimens from allograft biopsies, obtained after withdrawal of immunosuppressive therapy, there were high levels of P3 (FOXP3) messenger RNA (mRNA) but not granzyme B mRNA.
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    Acute Renal Endothelial Injury During Marrow Recovery in a Cohort of Combined Kidney and Bone Marrow Allografts
    (Wiley-Blackwell, 2011) Farris, A.B.; Taheri, D.; Kawai, Tatsuo; Fazlollahi, L.; Wong, Wesley; Tolkoff-Rubin, Nina; Spitzer, Thomas; Iafrate, Anthony; Preffer, Frederic; LoCascio, S. A.; Sprangers, B.; Saidman, Susan; Smith, Raymond; Cosimi, A.; Sykes, Megan; Sachs, David; Colvin, Robert
    An idiopathic capillary leak syndrome (“engraftment syndrome”) often occurs in recipients of hematopoietic cells, manifested clinically by transient azotemia and sometimes fever and fluid retention. Here we report the renal pathology in 10 recipients of combined bone marrow and kidney allografts. Nine developed graft dysfunction on day 10–16 and renal biopsies showed marked acute tubular injury, with interstitial edema, hemorrhage and capillary congestion, with little or no interstitial infiltrate (≤10%) and marked glomerular and peritubular capillary (PTC) endothelial injury and loss by electron microscopy. Two had transient arterial endothelial inflammation; and 2 had C4d deposition. The cells in capillaries were primarily CD68+MPO+ mononuclear cells and CD3+CD8+ T cells, the latter with a high proliferative index (Ki67+). B cells (CD20+) and CD4+ T cells were not detectable, and NK cells were rare. XY FISH showed that CD45+ cells in PTCs were of recipient origin. Optimal treatment remains to be defined; two recovered without additional therapy, six were treated with anti-rejection regimens. Except for one patient, who later developed thrombotic microangiopathy and one with acute humoral rejection, all fully recovered within 2–4 weeks. Graft endothelium is the primary target of this process, attributable to as yet obscure mechanisms, arising during leukocyte recovery.
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    Mixed Chimerism, Lymphocyte Recovery, and Evidence for Early Donor-Specific Unresponsiveness in Patients Receiving Combined Kidney and Bone Marrow Transplantation to Induce Tolerance
    (Ovid Technologies (Wolters Kluwer Health), 2010) LoCascio, Samuel A.; Morokata, Tatsuaki; Chittenden, Meredith; Preffer, Frederic; Dombkowski, David M.; Andreola, Giovanna; Crisalli, Kerry; Kawai, Tatsuo; Saidman, Susan; Spitzer, Thomas; Tolkoff-Rubin, Nina; Cosimi, A.; Sachs, David; Sykes, Megan
    Background We have previously reported operational tolerance in patients receiving HLA-mismatched combined kidney and bone marrow transplantation (CKBMT). We now report on transient multilineage hematopoietic chimerism and lymphocyte recovery in five patients receiving a modified CKBMT protocol, and evidence for early donor-specific unresponsiveness in one of these patients. Methods Five patients with end-stage renal disease received CKBMT from HLA-mismatched, haploidentical living related donors following modified non-myeloablative conditioning. Polychromatic flow cytometry (FCM) was used to assess multilineage chimerism where evaluable and lymphocyte recovery post-transplant. Limiting dilution analysis was used to assess helper-T-lymphocyte reactivity to donor antigens. Results Transient multilineage mixed chimerism was observed in all patients but chimerism became undetectable by 2 weeks post-CKBMT. A marked decrease in T and B lymphocyte counts immediately following transplant was followed by gradual recovery. Initially recovering T cells were depleted of CD45RA+/CD45RO− “naïve-like” cells, which have shown strong recovery in two patients and CD4/CD8 ratios increased immediately following transplant but then declined markedly. NK cells were enriched in the peripheral blood of all patients following transplant. For Subject 2, a pre-transplant limiting dilution assay revealed T helper cells recognizing both donor and third-party PBMCs. However, the anti-donor response was completely undetectable by Day 24, while third-party reactivity persisted. Conclusion These results characterize the transient multilineage mixed hematopoietic chimerism and recovery of lymphocyte subsets in patients receiving a modified CKBMT protocol. The observations are relevant to the mechanisms of donor-specific tolerance in this patient group.