Desensitizing highly sensitized heart transplant candidates with the combination of belatacept and proteasome inhibition

HLA antibodies pose a significant barrier to transplantation and current strategies to reduce allosensitization are limited. We hypothesized that augmenting proteasome inhibitor (PI) based desensitization with costimulation blockade (belatacept) to mitigate germinal center (GC) responses might incre...

Celý popis

Uloženo v:
Podrobná bibliografie
Vydáno v:American journal of transplantation Ročník 20; číslo 12; s. 3620 - 3630
Hlavní autoři: Alishetti, Shudhanshu, Farr, Maryjane, Jennings, Douglas, Serban, Geo, Uriel, Nir, Sayer, Gabriel, Vasilescu, Rodica, Restaino, Susan, Chong, Anita S., Habal, Marlena V.
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Elsevier Limited 01.12.2020
Témata:
Abatacept - therapeutic use
Antibodies
CD38 antigen
Complement component C1q
costimulation
Cytotoxicity
desensitization
Desensitization (Psychology)
Graft Rejection - drug therapy
Graft Rejection - prevention & control
Heart Transplantation
heart transplantation/cardiology
Heart transplants
Helper cells
histocompatibility
Histocompatibility antigen HLA
Histocompatibility Testing
HLA Antigens
Immunological memory
immunosuppressant—fusion proteins and monoclonal antibodies: belatacept
immunosuppression/immune modulation
Isoantibodies
Leukocytes, Mononuclear
Lymphocytes B
Memory cells
Monoclonal antibodies
natural killer (NK) cells/NK receptors
Natural killer cells
PD-1 protein
Peripheral blood mononuclear cells
Phenotypes
Proteasome Endopeptidase Complex
Proteasome inhibitors
sensitization
translational research/science
translational research/science
costimulation
immunosuppressant-fusion proteins and monoclonal antibodies: belatacept
immunosuppression/immune modulation
histocompatibility
natural killer (NK) cells/NK receptors
heart transplantation/cardiology
sensitization
desensitization
ISSN:1600-6135, 1600-6143, 1600-6143
On-line přístup:Získat plný text
Tagy: Přidat tag
Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!
Popis
Shrnutí:HLA antibodies pose a significant barrier to transplantation and current strategies to reduce allosensitization are limited. We hypothesized that augmenting proteasome inhibitor (PI) based desensitization with costimulation blockade (belatacept) to mitigate germinal center (GC) responses might increase efficacy and prevent rebound. Four highly sensitized (calculated panel reactive antibody [cPRA] class I and/or II >99%, complement‐dependent cytotoxicity panel reactive antibody [CDC PRA+], C1q+) heart transplant candidates were treated with the combination of belatacept and PI therapy, which significantly reduced both class I and II HLA antibodies and increased the likelihood of identifying an acceptable donor. Three negative CDC crossmatches were achieved against 3, 6, and 8 donor‐specific antibodies (DSA), including those that were historically C1q+ binding. Posttransplant, sustained suppression of 3 of 3, 4 of 6, and 8 of 8 DSA (cases 1‐3) was achieved. Analysis of peripheral blood mononuclear cells before and after desensitization in one case revealed a decrease in naïve and memory B cells and a reduction in T follicular helper cells with a phenotype suggesting recent GC activity (CD38, PD1, and ICOS). Furthermore, a shift in the natural killer cell phenotype was observed with features suggestive of activation. Our findings support synergism between PI based desensitization and belatacept facilitating transplantation with a negative CDC crossmatch against historically strong, C1q binding antibodies. The combination of costimulatory blockade and proteasome inhibition can be used to desensitize highly sensitized heart transplant candidates, resulting in negative crossmatches against multiple, historically strong donor‐specific antibodies, enabling transplantation and achieving sustained suppression after transplant.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:1600-6135
1600-6143
1600-6143
DOI:10.1111/ajt.16113