The Effect of Immunosuppressive Drugs on MDSCs in Transplantation

Myeloid-derived suppressor cells (MDSCs) are a group of innate immune cells that regulates both innate and adaptive immune responses. In recent years, MDSCs were shown to play an important negative regulatory role in transplant immunology even upstream of regulatory T cells. In certain cases, MDSCs are closely involved in transplantation immune tolerance induction and maintenance. It is known that some immunosuppressant drugs negatively regulate MDSCs but others have positive effects on MDSCs in different transplant cases. We herein summarized our recent insights into the regulatory roles of MDSCs in transplantation specially focusing on the effects of immunosuppressive drugs on MDSCs and their mechanisms of action. Studies on the effects of immunosuppressive drugs on MDSCs will significantly expand our understanding of immunosuppressive drugs on immune regulatory cells in transplantation and offer new insights into transplant tolerance. We hope to emphasize our concern for the negative effects of immunosuppressive agents on MDSCs, which may potentially attenuate the immune tolerance induction in transplanted recipients.

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A low‐dose immune tolerance induction (ITI) protocol incorporating immunosuppressive agents in haemophilia A children with high‐titre factor VIII inhibitor and poor‐ITI prognostic risk

Haemophilia ◽

10.1111/hae.14157 ◽

2020 ◽

Author(s):

Zekun Li ◽

Zhenping Chen ◽

Xiaoling Cheng ◽

Guoqing Liu ◽

Xinyi Wu ◽

...

Keyword(s):

Factor Viii ◽

Immune Tolerance ◽

Low Dose ◽

Immunosuppressive Agents ◽

Tolerance Induction ◽

High Titre ◽

Factor Viii Inhibitor ◽

Haemophilia A ◽

Immune Tolerance Induction ◽

Viii Inhibitor

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IMMUNE TOLERANCE INDUCTION IN HEMOPHILIA A WITH INHIBITOR

10.1055/s-0038-1644715 ◽

1987 ◽

Author(s):

C K Kasper ◽

N L Sanders ◽

N P Ewing

Keyword(s):

Hiv Infection ◽

Immune Tolerance ◽

Hemophilia A ◽

Tolerance Induction ◽

Immunosuppressive Drugs ◽

Immune Tolerance Induction ◽

The Third ◽

Rapid Induction ◽

Cell Counts ◽

Aids Related Complex

Factor VIII (FVIII), 50 U/Kg/day, was given without immunosuppressive drugs to 11 patients with hemophilia A and inhibitor. Interval since inhibitor diagnosis was 4-6 years (yr) in 3 cases and 12-27 yr in others. Six had received no FVIII since inhibitor diagnosis. Intervals since last FVIII use were 2 months (mo) in 3 cases and 3-15 yr in others. Historic peak inhibitor levels were 3,8,9,10,25,27,64,375,809,1100 and 2780 Bethesda units (BU). Levels at start of protocol (baseline) were under one BU in 7 cases and 2,42,265 and 398 in others. Evidence of HIV. infection exists in 10 patients: 8 of 9 tested have HIV antibody, 7 of 11 tested have low T4 cell counts and 4 currently have AIDS-related complex. Results after 4-31 mo (median 10) are as follows. Peak inhibitor levels on protocol exceeded baseline in only 6 cases and exceeded historic peaks in only 2 cases. All peaks occurred during the first mo and levels fell markedly by the second. All patients but one had levels below baseline by the third mo. Among 7 patients with one BU or less baseline, no inhibitor was detected after one mo in 4 cases and after 3 mo in 2 cases; another child still has trace inhibitor after 8 mo. A child with baseline 2 BU had no inhibitor after 4 mo. Three older patients have not responded completely. In 2 adults who began the protocol 2 mo after intense FVIII use for hemorrhages, baselines of 275 and 398 BU fell rapidly in the first 4 mo but then plateaued around 20-30 BU despite 9 and 26 mo further therapy. In a teenager who began the protocol 4 yr after intense FVIII use, the baseline of 42 BU has not fallen in 4 mo of therapy. Thus, rapid induction of immune tolerance was achieved in 7 of 8 patients with low baselines; the program was less useful in patients with high baselines. Of 4 patients resistant to full induction of immune tolerance, all have evidence of HIV infection; 3 were tested and have HIV antibody, 2 have low T4 counts and 2 have ARC. Thus, the immune suppression of HIV infection may not potentiate induction of FVIII tolerance. All patients achieving FVIII tolerance remain of FVIII prophylaxis. In some, low-level inhibitors emerged on attempts at withdrawal. Induction of immune tolerance with FVIII is advised for patients with currently-low inhibitor levels because of the high success rate.

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Cyclosporine A, in Contrast to Rapamycin, Affects the Ability of Dendritic Cells to Induce Immune Tolerance Mechanisms

Archivum Immunologiae et Therapiae Experimentalis ◽

10.1007/s00005-021-00632-7 ◽

2021 ◽

Vol 69 (1) ◽

Author(s):

Maja Machcińska ◽

Monika Kotur ◽

Aleksandra Jankowska ◽

Marta Maruszewska-Cheruiyot ◽

Artur Łaski ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell Activation ◽

Immune Tolerance ◽

Cyclosporine A ◽

Cell Activation ◽

Immunosuppressive Agents ◽

Immunosuppressive Drugs ◽

Transplant Tolerance ◽

Phagocytic Capacity ◽

Immature Dendritic Cells

AbstractFollowing organ transplantation, it is essential that immune tolerance is induced in the graft recipient to reduce the risk of rejection and avoid complications associated with the long-term use of immunosuppressive drugs. Immature dendritic cells (DCs) are considered to promote transplant tolerance and may minimize the risk of graft rejection. The aim of the study was to evaluate the effects of immunosuppressive agents: rapamycin (Rapa) and cyclosporine A (CsA) on generation of human tolerogenic DCs (tolDCs) and also to evaluate the ability of these cells to induce mechanisms of immune tolerance. tolDCs were generated in the environment of Rapa or CsA. Next, we evaluated the effects of these agents on surface phenotypes (CD11c, MHC II, CD40, CD80, CD83, CD86, CCR7, TLR2, TLR4), cytokine production (IL-4, IL-6, IL-10, IL-12p70, TGF-β), phagocytic capacity and resistant to lipopolysaccharide activation of these DCs. Moreover, we assessed ability of such tolDCs to induce T cell activation and apoptosis, Treg differentiation and production of Th1- and Th2-characteristic cytokine profile. Data obtained in this study demonstrate that rapamycin is effective at generating maturation-resistant tolDCs, however, does not change the ability of these cells to induce mechanisms of immune tolerance. In contrast, CsA affects the ability of these cells to induce mechanisms of immune tolerance, but is not efficient at generating maturation-resistant tolDCs.

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