Advances and challenges in immunotherapy for solid organ and hematopoietic stem cell transplantation

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Science Translational Medicine  25 Mar 2015:
Vol. 7, Issue 280, pp. 280rv2
DOI: 10.1126/scitranslmed.aaa6853


  • Fig. 1. The pathophysiology of and initiating factors involved in GVHD after HSCT.

    (A and B) Shown are the immune processes and molecules involved in the development of acute (A) or chronic (B) GVHD after HSCT. (A) Acute GVHD begins with a conditioning regimen such as chemotherapy combined with total body irradiation, which induces tissue damage. This tissue damage causes the release of danger signals, such as cytokines and chemokines, that activate recipient innate immune cells, including antigen-presenting cells (APCs). Donor APCs, which are a component of the stem cell graft, are also activated by this highly inflammatory milieu. A combination of donor and recipient APCs then activates donor CD4 and CD8 T cells. Cytokine production and direct cytolysis of host cells by these T cells, as well as by host macrophages, neutrophils, and natural killer (NK) cells, cause end-organ damage. The resulting tissue destruction further amplifies acute GVHD, creating a positive feedback loop that can be difficult to stop even with immunosuppressive drug treatment. IFN-γ, interferon-γ; TNF, tumor necrosis factor; IL-1, interleukin-1. (B) Thymic destruction, either from pretransplant conditioning or acute GVHD, and chronic stimulation of donor T cells contribute to chronic GVHD after HSCT. Thymic damage alters the selection of T cells, which can result in the release of lymphocytes that react to host tissues. Depending on the antigen, this reaction to the host can be considered allo- or autoreactive. Once activated, these T cells stimulate fibroblast proliferation and macrophage activation, both of which result in tissue fibrosis. Donor T cells also contribute to fibroblast activation and play a key role in activating B cells, which produce antibodies with specificities for host tissues. All of these events contribute to the highly fibrotic syndrome of chronic GVHD. TGF-β1, transforming growth factor–β1; PDGF, platelet-derived growth factor.

  • Fig. 2. The pathophysiology of and initiating factors involved in rejection of solid organ transplants.

    (A and B) Shown are the factors involved in the development of acute (A) and chronic (B) rejection of solid organ transplants. (A) The process of acute allograft rejection begins with recipient CD4 and CD8 T cells becoming activated through interactions with donor and recipient APCs (respectively termed direct and indirect allorecognition). After activation, CD8 T cells and, to a lesser extent, CD4 T cells directly destroy both graft blood vessels and parenchyma. Recipient CD4 T cells primarily contribute to acute rejection by producing a variety of cytokines that activate macrophages and neutrophils. These innate cells then attack and lyse graft cells. The combination of lymphocyte- and innate cell–directed graft destruction results in allograft dysfunction and acute rejection. MHC, major histocompatibility complex. (B) In chronic allograft rejection, CD4 T cells help to induce antibody class switching, affinity maturation, and ultimately the production of donor-specific antibodies (DSA) by recipient B cells. Binding of DSA to graft cells enhances neutrophil-, macrophage-, and NK cell–mediated destruction of the graft (through Fc receptor binding) and results in complement deposition. Subsequent activation of the complement cascade results in direct lysis of graft cells through the complement membrane attack complex and further augments innate cell recognition and destruction of the graft. Although this process evolves over months to years, it results in chronic allograft dysfunction and eventual complete rejection.

  • Fig. 3. Mechanisms of action for promising immunomodulatory therapies.

    Shown are known mechanisms by which new agents alter critical aspects of the pathogenesis of GVHD and solid organ transplant rejection. Most of these therapies focus on inhibiting various functions of conventional T cells (Tcon), which are the primary drivers of many aspects of GVHD and allograft rejection. Abatacept and belatacept, CTLA4-Ig fusion protein inhibitors of CD80/86; azacitidine, DNA-hypomethylating agent; sotrastaurin, pan-PKC inhibitor with preferential selectivity for PKC-θ; anti-CD132, anti–IL-2 common γ-chain (CD132) monoclonal antibody (mAb); AMG 557, anti-ICOS/B7RP1 mAb; bortezomib, proteasome inhibitor; compound 79-6, Bcl-6 inhibitor; cyclophosphamide, DNA-alkylating agent; E7438, EZH2 methyltransferase inhibitor; eculizumab, complement inhibitor; fingolimod, sphingosine-1-phosphate receptor inhibitor; GSK2816126, EZH2 methyltransferase inhibitor; ibrutinib, BTK/ITK inhibitor; KD025, ROCK2 inhibitor; kynurenines, products of l-tryptophan catabolism; lucatumumab, anti-CD40 mAb; maraviroc, CCR5 antagonist; MSB0010841, anti–IL-17A/F nanobody; NN8828, anti–IL-21 mAb; rapamycin, mTOR inhibitor; rituximab, anti-CD20 mAb; ruxolitinib, JAK1/2 inhibitor; secukinumab, anti–IL-17A mAb; single-chain anti-CD28 antibody, anti-CD28 mAb; TMP778, retinoic acid receptor–related orphan receptor γt (RORγt) antagonist; TMP920, RORγt antagonist; tocilizumab, anti–IL-6R mAb; tofacitinib, JAK3 inhibitor; ustekinumab, anti–IL-12/23 mAb; vorinostat/suberanilohydroxamic acid, HDAC inhibitor; Treg, regulatory T cell.


  • Table 1. New approaches for preventing or treating GVHD and solid organ transplant rejection.
    TocilizumabAnti–IL-6R mAb
    UstekinumabAnti–IL-12/23 mAb
    NN8828Anti–IL-21 mAb
    SecukinumabAnti–IL-17A mAb
    Altering immune
    cell trafficking
    MaravirocCCR5 small-
    molecule inhibitor
    receptor modulator
    of T and
    B cell
    RuxolitinibJAK1/2 small-
    molecule inhibitor
    TofacitinibJAK3 small-molecule
    IbrutinibITK/BTK small-molecule
    SotrastaurinPKC-θ small-molecule
    KD025ROCK2 small-molecule
    TMP778, TMP920RORγ small-molecule
    B cell depletionRituximabAnti-CD20 mAb
    in vivo
    of Tregs
    Rapamycin (+IL-2)mTOR small-
    molecule inhibitor
    Azacitidine (+IL-2)DNA-hypomethylating
    proliferative cytokine
    VorinostatHDAC small-molecule
    CyclophosphamideDNA-alkylating agent
    Cell therapiesTregsCD4+CD25+Foxp3+
    suppressive T cell
    Type 1 T regulatory
    (Tr1) cells
    suppressive T cell
    Mesenchymal stem
    Suppressive stem
    cell population
    dendritic cells (DCs)
    Suppressive DCs
    Stem cell transplant with solid organ transplantChimerism to induce
    Inhibition of T cell
    fusion protein
    fusion protein
    Single-chain CD28
    Anti-CD28 mAb
    LucatumumabAnti-CD40 mAb
    AMG-557Anti–ICOS-L mAb
    EculizumabAnti-C5a mAb
    Targeting metabolic
    Kynurenine infusionTryptophan
    TLR7/8 AgonistEnhances kynurenine production by APCs
    Blocking germinal
    center formation
    Compound 79-6Bcl-6 small-
    molecule inhibitor
    GSK2816126EZH2 small-
    molecule inhibitor
    E7438EZH2 small-
    molecule inhibitor
    OtherBortezomibProteasome small-
    molecule inhibitor

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