scholarly journals Development of immunosuppressive myeloid cells to induce tolerance in solid organ and hematopoietic cell transplant recipients

2021 ◽  
Author(s):  
Kent P Jensen ◽  
David Hongo ◽  
Xuhuai Ji ◽  
Pingping Zheng ◽  
Rahul D Pawar ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Conditioning Regimen ◽  
Myeloid Cells ◽  
Hematopoietic Cell ◽  
Mixed Chimerism ◽  
Solid Organ ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Post Transplant

Replacement of failed organs followed by safe withdrawal of immunosuppressive drugs have long been the goals of organ transplantation. We studied changes in the balance of T and myeloid cells in blood of HLA-matched and -mismatched patients given living donor kidney transplants (KTx) followed by total lymphoid irradiation (TLI), anti-thymocyte globulin (ATG) conditioning, and donor hematopoietic cell transplant (HCT) to induce mixed chimerism and immune tolerance. The clinical trials were based on a conditioning regimen used to establish mixed chimerism and tolerance in mice. In pre-clinical murine studies, there was a profound depletion of T cells and an increase in immunosuppressive, polymorphonuclear (pmn), myeloid derived suppressor cells (MDSCs) in the spleen and blood following transplant. Selective depletion of the pmn-MDSCs in mice abrogated mixed chimerism and tolerance. In our clinical trials, patients given an analogous tolerance conditioning regimen developed similar changes including profound depletion of T cells and a marked increase in MDSCs in blood post-transplant. Post-transplant pmn-MDSCs transiently increased expression of lectin-type, oxidized LDL receptor-1 (LOX-1), a marker of immunosuppression, and production of the T cell inhibitor, arginase-1. These post-transplant pmn-MDSCs suppressed the activation, proliferation, and inflammatory cytokine secretion of autologous, TCR microbead-stimulated, pre-transplant T cells when co-cultured in vitro. In conclusion, we elucidated changes in receptors, and function of immunosuppressive myeloid cells in patients enrolled in the tolerance protocol that were nearly identical to the that of MDSCs required for tolerance in mice. The clinical trials are registered in Clinicaltrials.gov under NCT #s 00319657 and 01165762.

Identification of a Single MiHA Specificity That Induces Resistance to MHC-Matched Allogeneic HCT.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3216-3216
Author(s):  
Alwi M. Shatry ◽  
Robert B. Levy
Keyword(s):  
T Cells ◽  
T Cell ◽  
Donor Cell ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Post Transplant ◽  
Single Donor ◽  
Donor Cells ◽  
Allogeneic Marrow

Abstract T cell populations specific for transplantation antigens have been detected in sensitized individuals following multiple blood transfusions, marrow transplants as well as in multiparous females. Resistance to allogeneic hematopoietic cell transplant (HCT) in such sensitized individuals is consistent with the presence of a host memory T cell (TM) population specific for donor cell antigens. We hypothesized that a single donor minor histocompatibility (MiHA) epitope could elicit antigen-specific CD8 TM capable of resisting MHC-matched allogeneic hematopoietic cell engraftment. To address this question, CD8 TM were generated against a single MiHA epitope to determine if such cells could mediate resistance after ablative TBI conditioning. B6 mice were sensitized 2X to the H60 immunodominant MiHA epitope utilizing bone marrow-derived dendritic cells pulsed with the H60 (LTFNYRNL) peptide. Three weeks following booster sensitization, CD8 T cells were detected by tetramer staining in peripheral blood samples. These T cells exhibited a phenotype characteristic of memory cells (CD44hi, Ly 6C+). B6 (H2b) mice containing CD8+ H60+ T cells were subsequently conditioned with 9.0 Gy TBI and transplanted with 5 × 106 BALB.B (H2b) BM-TCD. One week post-transplant, naive recipients of BALB.B (H60+) or B6-H60 congenic TCD-BM contained >10-fold higher levels of circulating donor cells than the B6 dendritic cell/peptide sensitized recipients. Donor progenitor cells were also found to be significantly reduced in sensitized recipients of allogeneic TCD-BM at this time. Two weeks post-HCT, recipients of syngeneic marrow exhibited >10-fold greater frequency of circulating donor cells compared to recipients of MHC-matched allogeneic marrow (< 5% donor chimerism was detected). These findings demonstrate that host T cells with specificity against a single donor MiHA determinant are sufficient to induce resistance to MHC-matched allogeneic marrow engraftment. Such observations regarding the effector response of HVG contrast those by donor T cell responses post-transplant in which single MiHA differences fail to induce GVHD. Finally, heterologous immunity to virus has been reported to generate allo-reactive TM cells. Since such TM repertoires could include specificity for MiHA immunodominant epitopes, the presence of TM populations that can mediate resistance in “naive” recipients may be more prevalent than hitherto appreciated.

scholarly journals Impact of conditioning regimen on peripheral blood hematopoietic cell transplant

2019 ◽  
Vol 10 (2) ◽  
pp. 86-97
Author(s):  
Michael Burns ◽  
Anurag K Singh ◽  
Carrie C Hoefer ◽  
Yali Zhang ◽  
Paul K Wallace ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant

scholarly journals Hematopoietic cell transplant for acute myeloid leukemia and myelodysplastic syndrome: conditioning regimen intensity

2018 ◽  
Vol 2 (16) ◽  
pp. 2095-2103 ◽  
Author(s):  
Mary Eapen ◽  
Ruta Brazauskas ◽  
Michael Hemmer ◽  
Waleska S. Perez ◽  
Patricia Steinert ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Clinical Remission ◽  
Myeloid Leukemia ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Key Points ◽  
Acute Myeloid

Key Points Bu4/Cy, Flu/Bu4, and Flu/Mel are optimal regimens for patients with AML in clinical remission or those with MDS. Flu/Mel, considered a less-intense regimen, is ideal for less fit patients.

Donor T Cells from B Cell Deficient Mice Inhibit B Cell Development in Normal Recipients after Hematopoietic Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3265-3265
Author(s):  
Antonia M.S. Mueller ◽  
Jessica A. Allen ◽  
David Miklos ◽  
Judith A. Shizuru
Keyword(s):  
T Cells ◽  
B Cell ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Hematopoietic Stem ◽  
Donor Chimerism ◽  
Donor T Cells ◽  
The Impact

Abstract Allogeneic hematopoietic cell transplant (HCT) recipients often exhibit B cell (BC) lymphopenia due, in part, to graft-versus-host-disease (GVHD). Here, we studied the impact of donor T cells (TC) on BC deficiency post minor antigen-mismatched HCT. Following lethal irradiation, BALB.B mice were given FACS purified hematopoietic stem cells (HSC: cKIT+Thy1.1loLin-Sca-1+) alone, with whole splenocytes (SP), CD4 or CD8 TC from minor antigen-mismatched C57BL/6 (B6) mice. Chimerism analyses were performed on day (d) 30, 60, and 90. When pure HSC were transplanted, BCs reconstituted promptly (median 33% of lymphocytes [d30]; 61% [d60]; 74% [d90]), whereas TC engraftment was retarded and did not achieve full donor chimerism. Addition of SP or CD4 TCs, or to a lesser degree CD8 TCs, delayed BC reconstitution, with extremely low percentages of BCs beyond d60. This BC suppression correlated with the degree of acute GVHD, and BC numbers increased with recovery from GVHD. Additionally, this BC suppression was in stark contrast to TC development, with TC transfer resulting in early conversion to full donor chimerism. To test if previous events in the donor sensitize TCs against BC features (e.g. minor antigens), thereby promoting anti-BC cytotoxicity post-HCT, TCs from B6 muMT mice were co-transplanted with HSC. muMT mice are devoid of mature BCs because they lack the mu chain; consequently, their TCs were not exposed to BCs prior to transfer. Remarkably, BC engraftment was completely prevented through d90. TCs regenerated faster, but the vast majority originated from spleen and not HSC. To differentiate this lack of BC engraftment from GVHD-associated, alloreactive BC lymphopenia, syngenic B6 recipients were used. Again, initially complete blockade of BC engraftment was observed, although this suppression was overcome earlier post-HCT as compared to the minor-mismatched pair (median % BC d60: ’HSC only’ recipients 52%; +CD4 17%; +CD8 48%). To clarify if this phenomenon was a purely cytotoxic reaction of muMT TC against BCs, we used WT B6 HSC +/− SP as donors and lethally or sublethally irradiated muMT mice as recipients. All groups, including sublethally irradiated animals, where host muMT TC were still present, engrafted BCs making a direct anti-BC cytotoxicity unlikely as the sole cause of the BC inhibition. FACS analysis of bone marrow was used to assess the developmental stages of BCs (Hardy fractions (Fr.) A-F) and revealed GVHD recipients with peripheral B lymphopenia have a shift of B220+ cells from more mature Fr. D-F to immature Fr. A-C stages and a lower proportion of IgM expressing BC. Recipients of the muMT TCs showed, in addition to a shift to more immature stages, a clear block in BC development with an absent switch to the expression of IgM (stage D to E)(Fig. 1). In conclusion, muMT TCs are capable of blocking BC maturation when transferred into WT mice, suggesting defective TC activity in muMT animals necessary for the co-development of both BCs and TCs. Furthermore, this study provides evidence that mature TCs are capable of interfering with BC regeneration post-HCT. Hence, our HCT combinations using WT and muMT B6 mice provide a powerful tool to study the role of TC function in the process of donor BC development post-HCT.

scholarly journals Inferior Outcomes for Patients Developing New-Onset Post-Transplant Diabetes Mellitus after Haploidentical Hematopoietic Cell Transplant

2020 ◽  
Vol 26 (3) ◽  
pp. S354-S355
Author(s):  
Brendan L. Mangan ◽  
Dilan A. Patel ◽  
Heidi Chen ◽  
Katie S. Gatwood ◽  
Michael T. Byrne ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Post Transplant ◽  
New Onset
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