Deoxyspergualin: A New Immunosuppressive Drug for the Treatment of Auto-Immune Disease

Kerr, Peter G.; Lan, Hui Y.; Tesch, Gregory H; Atkins, Robert C.

doi:10.1159/000188634

Cited by 7 publications

(3 citation statements)

References 32 publications

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“…Here, anti-C5 Ab treatment was combined with LF and CsA. LF and its analogue 15-deoxyspergualin (DSG) have documented protective effects in kidney damage and primate kidney allograft models (27)(28)(29)(30)(31), which occur through inhibition of antigen-presenting cell maturation, activation and local recruitment (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41), and in particular, attenuation of B-cell differentiation and antibody production (32)(33)(34)(35)(36). Additionally, to attenuate T-cell alloreactivity directly, we also included CsA in the treatment regimen with LF and anti-C5 monoclonal antibody.…”

Section: Introductionmentioning

confidence: 99%

C5 Blockade with Conventional Immunosuppression Induces Long-Term Graft Survival in Presensitized Recipients

Rother

Arp

Jiang

et al. 2008

American Journal of Transplantation

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We explored whether a functionally blocking anti-C5 monoclonal antibody (mAb) combined with T- and B-cell immunosuppression can successfully prevent antibody-mediated (AMR) and cell-mediated rejection (CMR) in presensitized murine recipients of life-supporting kidney allografts. To mimic the urgent clinical features of AMR experienced by presensitized patients, we designed a murine model in which BALB/c recipients were presensitized with fully MHC-mismatched C3H donor skin grafts one week prior to C3H kidney transplantation. Presensitized recipients demonstrated high levels of circulating and intragraft antidonor antibodies and terminal complement activity, rejecting grafts within 8.5 +/- 1.3 days. Graft rejection was predominantly by AMR, characterized by interstitial hemorrhage, edema and glomerular/tubular necrosis, but also demonstrated moderate cellular infiltration, suggesting CMR involvement. Subtherapeutic treatment with cyclosporine (CsA) and LF15-0195 (LF) did not significantly delay rejection. Significantly, however, the addition of anti-C5 mAb to this CsA/LF regimen prevented terminal complement activity and inhibited both AMR and CMR, enabling indefinite (>100 days) kidney graft survival despite the persistence of antidonor antibodies. Long-term surviving kidney grafts expressed the protective proteins Bcl-x(S/L) and A-20 and demonstrated normal histology, suggestive of graft accommodation or tolerance. Thus, C5 blockade combined with routine immunosuppression offers a promising approach to prevent graft loss in presensitized patients.

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Section: Introductionmentioning

confidence: 99%

C5 Blockade with Conventional Immunosuppression Induces Long-Term Graft Survival in Presensitized Recipients

Rother

Arp

Jiang

et al. 2008

American Journal of Transplantation

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“…can inhibit the development of both the humoral and were designed to determine whether LF15-0195 treatment could prevent the induction of anti-GBM disease the aggressive cellular immune responses associated with the evolution of rapidly progressive immune-mediated (experiment 1) and the progression of established anti-GBM disease through continuous treatment (experiment kidney disease [9] and can inhibit the activity of intrinsic renal cells [14]. DSG treatment during the induction of 2a) and pulse therapy (experiment 2b).…”

mentioning

confidence: 99%

LF15-0195 prevents the induction and inhibits the progression of rat anti-GBM disease

Tesch

Hill

et al. 2001

Kidney International

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LF15-0195 prevents the induction and suppresses the progression of rat anti-GBM disease through multiple mechanisms of action, suggesting that this drug may have significant therapeutic potential in human glomerulonephritis. The similar efficacy of continuous and pulse intervention treatment in this model indicates that short-term LF15-0195 treatment may achieve optimal benefit without prolonged bone marrow suppression.

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“…Consider the dramatic beneficial effects that have now been documented in experimental glomerulonephritis with treatments that selectively suppress the cell-mediated response without altering antibody deposition. Examples include the infusion of interleukin-4 (IL-4) and IL-10 (18), inhibition of MIF (19), and use of agents such as deoxyspergualin, which selectively inhibits cell-mediated immunity (20). Other agents with effects primarily on the cell-mediated immune response are now available or nearly so-for example, IL-2 receptor antagonists and CD40 ligand-but have not yet been tried in glomerular disease.…”

mentioning

confidence: 99%

Sensitized Cells Come of Age

Couser

1999

Journal of the American Society of Nephrology

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Deoxyspergualin: A New Immunosuppressive Drug for the Treatment of Auto-Immune Disease

Cited by 7 publications

References 32 publications

C5 Blockade with Conventional Immunosuppression Induces Long-Term Graft Survival in Presensitized Recipients

C5 Blockade with Conventional Immunosuppression Induces Long-Term Graft Survival in Presensitized Recipients

LF15-0195 prevents the induction and inhibits the progression of rat anti-GBM disease

Sensitized Cells Come of Age

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