Inflammatory response to the administration of mesenchymal stem cells in an equine experimental model: effect of autologous, and single and repeat doses of pooled allogeneic cells in healthy joints

Summary Background Allogeneic bone marrow‐derived mesenchymal stem cells (BMDMSCs) could provide multiple advantages over autologous BMDMSCs, including creating an ‘off‐the‐shelf’ treatment together with the ability to control for donor variation. Objectives The objective of the study was to compare the clinical and synovial fluid response of the normal equine joint to autologous and pooled‐allogeneic BMDMSCs while controlling for individual variation and joint variations in response to intra‐articular injections. We hypothesised that, by controlling for individual animal and joint variation, we could identify differences between allogeneic vs. autologous BMDMSCs in noninflamed joints. Study design Randomised‐controlled experiment. Methods Bone marrow was harvested from eight horses. Autologous BMDMSCs were culture expanded, cryopreserved and thawed immediately prior to administration. For allogeneic BMDMSC treatments, four horses' BMDMSCs were culture expanded, pooled, cryopreserved and thawed immediately prior to use. Ten million (autologous or pooled‐allogeneic) BMDMSCs were administered into contralateral forelimb metacarpophalangeal joints so that every autologous and allogeneic injection could be compared within the same animal. Clinical parameters included subjective lameness, objective lameness (Lameness Locator™), response to flexion, joint circumference and joint effusion. Arthrocentesis was performed for assessment of the nucleated cell count, differential cell count, total protein, and synovial concentrations of prostaglandin E2 (PGE2) and c‐reactive protein (CRP). All parameters were measured at baseline, 6, 12, 24, 72, 168 and 336 h post‐injection. Results No difference was detected in any parameters between forelimb metacarpophalangeal joints administered autologous or pooled‐allogeneic BMDMSCs. Main limitations This study did not attempt to measure efficacy of BMDMSCs for musculoskeletal disease and should be followed by properly controlled efficacy trials. Conclusions The study did not identify any clinical or cytological differences in the normal joint response to allogeneic or autologous BMDMSCs. A larger study to prove equivalence is warranted as allogeneic BMDMSCs may be a feasible alternative to autologous BMDMSCs.

Section: Discussionsupporting

confidence: 87%

Allogeneic vs. autologous intra‐articular mesenchymal stem cell injection within normal horses: Clinical and cytological comparisons suggest safety

Colbath

Dow

Hopkins

et al. 2019

“…Interestingly, repeat injections of allogenic cells showed a lower degree of synovitis than the initial injection in all six horses. The characterisation of cells in this study showed that there was moderate expression of MHC I and low expression of MHC II [12]. This is in contrast with the allogenic cells from our donor which were determined to be negative for MHC II from passages 2 through 5.…”

Section: Discussioncontrasting

confidence: 73%

“…Previous studies have shown conflicting results regarding the intra‐synovial use of allogenic MSCs. Compared with control joints injected with lactated ringer's solution, 100% of joints injected with either autologous or pooled allogenic BM‐MSCs showed evidence of synovitis with mild increased total‐nuclear cell counts (TNCCs) and total protein values . The authors reported that horses in this study did not receive any systemic anti‐inflammatories.…”

Section: Discussionmentioning

confidence: 76%

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Retrospective analysis of local injection site adverse reactions associated with 230 allogenic administrations of bone marrow‐derived mesenchymal stem cells in 164 horses

Ursini

Amelse

Elkhenany

et al. 2018

“…Initial studies evaluating the efficacy of equine mesenchymal stem cells (MSCs) from mature horses for the treatment of musculoskeletal injuries used autologous cells [1][2][3][4][5][6][7], but more recently, numerous studies have been performed to evaluate the safety of allogeneic, mature equine MSCs in the hope of replacing autologous cells with allogeneic cells [8][9][10][11][12][13][14][15][16][17]. Allogeneic MSCs would allow for the immediate treatment of acute injuries with cells of known quality and sufficient quantity and eliminate the need for either bone marrow aspirate or adipose biopsy from the patient.…”

Section: Introductionmentioning

confidence: 99%

Allogeneic major histocompatibility complex‐mismatched equine bone marrow‐derived mesenchymal stem cells are targeted for death by cytotoxic anti‐major histocompatibility complex antibodies

Berglund

Schnabel

2016

Summary Background Allogeneic mesenchymal stem cells (MSCs) are a promising cell source for treating musculoskeletal injuries in horses. Controversy exists, however, over whether major histocompatibility complex (MHC)-mismatched MSCs are recognised by the recipient immune system and targeted for death by a cytotoxic antibody response. Objectives To determine if cytotoxic anti-MHC antibodies generated in vivo following MHC-mismatched MSC injections are capable of initiating complement-dependent cytotoxicity of MSCs. Study design Experimental controlled study. Methods Antisera previously collected at Days 0, 7, 14 and 21 post-injection from 4 horses injected with donor MHC-mismatched equine leucocyte antigen (ELA)-A2 haplotype MSCs and one control horse injected with donor MHC-matched ELA-A2 MSCs were utilised in this study. Antisera were incubated with ELA-A2 MSCs before adding complement in microcytotoxicity assays and cell death was analysed via eosin dye exclusion. ELA-A2 peripheral blood leucocytes (PBLs) were used in the assays as a positive control. Results Antisera from all 4 horses injected with MHC-mismatched MSCs contained antibodies that caused the death of ELA-A2 haplotype MSCs in the microcytotoxicity assays. In 2 of the 4 horses, antibodies were present as early as Day 7 post-injection. MSC death was consistently equivalent to that of ELA-A2 haplotype PBL death at all time points and antisera dilutions. Antisera from the control horse that was injected with MHC-matched MSCs did not contain cytotoxic ELA-A2 antibodies at any of the time points examined. Main limitations This study examined MSC death in vitro only and utilized antisera from a small number of horses. Conclusions The cytotoxic antibody response induced in recipient horses following injection with donor MHC-mismatched MSCs is capable of killing donor MSCs in vitro. These results suggest that the use of allogeneic MHC-mismatched MSCs must be cautioned against, not only for potential adverse events, but also for reduced therapeutic efficacy due to targeted MSC death.