Antibody-Induced Transplantation Tolerance That Is Dependent on Thymus-Derived Regulatory T Cells

Deng, Shaoping; Moore, Daniel J.; Huang, Xiaolun; Mohiuddin, Mohammad; Lee, Major K.; Velidedeoğlu, Ergun; Lian, Moh-Moh; Chiaccio, Meredith; Sonawane, Samsher; Orlin, Anton; Wang, Jing; Chen, Haiying; Caton, Andrew J.; Zhong, Robert; Markmann, James F.

doi:10.4049/jimmunol.176.5.2799

Cited by 30 publications

(29 citation statements)

References 44 publications

(34 reference statements)

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“…Because CTLA-4 can deliver negative signals in T cell activation and may be expressed by regulatory T cells (Tregs), 6 anti-CD45RB-induced up-regulation of CTLA-4 may play an important role in deactivation of graft-reactive lymphocytes (8,9). In addition, induction of T cell anergy and formation of Th2 or Treg cells have been suggested in previous studies (4,10).…”

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confidence: 99%

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Cutting Edge: Transplant Tolerance Induced by Anti-CD45RB Requires B Lymphocytes

Deng

Moore

Huang

et al. 2007

The Journal of Immunology

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Selective interference with the CD45RB isoform by mAb (anti-CD45RB) reliably induces donor-specific tolerance. Although previous studies suggest participation of regulatory T cells, a mechanistic understanding of anti-CD45RB-induced tolerance is lacking. We report herein the unexpected finding that tolerance induced by this agent is not established in B cell-deficient mice but can be recovered by preemptive B lymphocyte transfer to B cell-deficient hosts. Using B cells from genetically modified donors to reconstitute B cell-deficient recipients, we evaluate the role of B lymphocyte-expressed CD45RB, T cell costimulatory molecules, and the production of Abs in this novel tolerance mechanism. Our data document an Ab-induced tolerance regimen that is uniquely B lymphocyte-dependent and suggest mechanistic contributions to tolerance development from the B cell compartment through interactions with T cells.

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confidence: 99%

“…Thus, CD45 serves as a rheostat that determines the overall sensitivity of the adaptive immune system to antigenic stimulation. Given its crucial role in lymphocyte activation, CD45 has been targeted with therapies that have emerged as potent immunosuppressive agents in both autoimmune and transplant models (4,5).…”

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confidence: 99%

Cutting Edge: Transplant Tolerance Induced by Anti-CD45RB Requires B Lymphocytes

Deng

Moore

Huang

et al. 2007

The Journal of Immunology

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“…42,43 Anti-RB treatment is useful as an immunotherapeutic agent and induces transplant tolerance. 39,[44][45][46][47] It must be stressed that B cells play a critical role in these processes. 48 Therefore additional studies into the impact of CD45RB ligation on the surface of B cells are needed.…”

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confidence: 99%

Key developmental transitions in human germinal center B cells are revealed by differential CD45RB expression

Jackson

Harp

Patel

et al. 2009

Blood

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We previously reported that RO ؉ expression correlated with increased mutation, activation, and selection among human germinal center (GC) B cells. Here, we subdivided human tonsillar B cells, including IgD ؊ CD38 ؉ GC B cells, into different fractions based on RB expression. Although each subset contained RB ؉ cells, when used as an intrasubset marker, differential RB expression effectively discriminated between phenotypically distinct cells. For example, RB ؉ GC B cells were enriched for activated cells with lower AID expression. RB inversely correlated with mutation frequency, demonstrating a key difference between RB-and RO-expressing GC B cells. Reduced RB expression during the transition from pre-GC (IgM ؉ IgD ؉ CD38 ؉ CD27 ؊ ) to GCB cells was followed by a dramatic increase during the GC-to-plasmablast (IgD ؊ CD38 ؉؉ CD27 ؉ ) and memory (IgD ؊ CD38 ؊ CD27 ؉ ) transition. Interestingly, RB ؉ GC B cells showed increased signs of terminal differentiation toward CD27 ؉ post-GC early plasmablast (increased CD38 and RO) or early memory IntroductionImmune function is uncompromisingly governed by at least 3 interdependent principles including recognition, effector function, and transition. Early naive B and T cells that successfully bind foreign antigen become activated and undergo developmental transition toward more mature, faster responding memory subsets. In contrast, lymphocytes that bind self-antigen in the periphery are usually counterselected against and undergo a different type of transition, one toward apoptosis or anergy. Ineffectual negative selection against self-specific B cells has been associated with the development of autoimmune and neoplastic diseases. Unfortunately, potential factors responsible for the redirection or abrogation of transitions toward cell death and anergy have not been conclusively determined. Antibody sequence analyses revealed that B cells participating in autoreactive responses are often mutated and show signs of selection for self-antigen. 1,2 This suggests that somatic hypermutation (SHM) during proliferation and activationbased transitions in the dynamic germinal center reaction may play a role (whether direct or indirect) in disease pathogenesis.We therefore sought to develop an expedient approach that would allow for the reproducible identification of B-cell populations that exist at different transitional stages based on their states of activation, SHM-dependent diversification, and developmental progression toward adjacent downstream subsets. Delineating how surface marker profiles change as B cells transition between key stages (especially when immunoregulatory markers such as CD45 protein tyrosine phosphatase are included in such profiles) should increase our understanding of B-cell development and ultimately how to circumvent dysregulated processes that could lead to disease.Over the past 3 decades, our research laboratory has investigated multiple aspects of human B-cell development and the molecular processes that collectively shape the peripheral BCR repertoi...

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“…A previous study utilizing CD45RB mAbs showed that tolerance could not be achieved in aged mice due to thymic atrophy (24), because this mode of tolerance induction requires an active thymus to produce new Tregs (38). In the present study, 100% of aged mice became tolerant to allogeneic skin grafts, suggesting that tolerance induction in our model is not hindered by thymic atrophy and/or compensated by peripheral mechanisms.…”

Section: Discussionmentioning

confidence: 47%

“…Models of transplantation tolerance that do not depend on BMT-induced mixed chimerism have also demonstrated a requirement for an active thymus (24,38,39). To determine the role of intrathymic deletion in this model, 2-month-old mice were Tx prior to BMT (as aged mice did not recover from thymectomy under general anesthesia in our experience).…”

Section: Discussionmentioning

confidence: 99%

Establishment of Transplantation Tolerance via Minimal Conditioning in Aged Recipients

Morison

Homann

Hammett

et al. 2014

American Journal of Transplantation

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y Co-senior authors.Mixed hematopoietic chimerism is a powerful means of generating donor-specific tolerance, allowing longterm graft acceptance without lifelong dependence on immunosuppressive drugs. To avoid the need for whole body irradiation and associated side effects, we utilized a radiation-free minimal conditioning regime to induce long-term tolerance across major histocompatibility barriers. We found that low-dose busulfan, in combination with host T cell depletion and short-term sirolimus-based immunosuppression, facilitated efficient donor engraftment. Tolerance was achieved when mice were transplanted with whole or T cell-depleted bone marrow, or purified progenitor cells. Tolerance induction was associated with an expansion in regulatory T cells and was not abrogated in the absence of a thymus, suggesting a dominant or compensatory peripheral mode of tolerance. Importantly, we were able to generate durable chimerism and tolerance to donor skin grafts in both young and aged mice, despite age-related thymic atrophy and immune senescence. Clinically, this is especially relevant as the majority of transplant recipients are older patients whose immune recovery might be dangerously slow and would benefit from radiation-free minimal conditioning regimes that allow efficient donor engraftment without fully ablating the recipient immune system.

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Antibody-Induced Transplantation Tolerance That Is Dependent on Thymus-Derived Regulatory T Cells

Cited by 30 publications

References 44 publications

Cutting Edge: Transplant Tolerance Induced by Anti-CD45RB Requires B Lymphocytes

Cutting Edge: Transplant Tolerance Induced by Anti-CD45RB Requires B Lymphocytes

Key developmental transitions in human germinal center B cells are revealed by differential CD45RB expression

Establishment of Transplantation Tolerance via Minimal Conditioning in Aged Recipients

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