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Abstract

This study evaluates the clinical efficacy and safety of intravenous allogeneic mesenchymal stem cell (MSC) therapy as an adjunct to standard immunosuppressive treatment in dogs diagnosed with primary immune-mediated hemolytic anemia (IMHA), particularly in cases with inadequate response to conventional immunosuppressive protocols. A total of 157 client-owned dogs with IMHA received MSC therapy at Safari Veterinary Care Center or collaborating clinics. A core cohort of 43 dogs met strict inclusion criteria: confirmed primary IMHA, no significant comorbidities, and receipt of at least two MSC treatments. A retrospective analysis was performed on medical records of treated dogs. Packed cell volume (PCV) trends were used to assess treatment response, with success defined as sustained improvement to ≥30% PCV following MSC therapy. Safety was assessed by reviewing for adverse reactions postinfusion. In the core cohort, 76% (33/43) of dogs achieved successful hematological recovery. Across the broader cohort, clinical improvement was also observed, particularly in dogs with poor initial response to standard therapy. No serious adverse events were recorded following MSC infusion. Allogeneic MSC therapy appears to be a well-tolerated and potentially effective adjunctive treatment for canine IMHA, particularly in refractory cases. These findings support further investigation in controlled clinical trials.

Introduction

Background and clinical challenge

Immune-mediated hemolytic anemia (IMHA) is a life-threatening autoimmune disorder, which destroys red blood cells (RBCs) through aberrant immune responses. In affected dogs, the immune system targets RBC surface antigens, resulting in premature hemolysis that occurs either within the bloodstream through complement activation (intravascular hemolysis) or in organs such as the spleen and liver via phagocytosis by macrophages (extravascular hemolysis).¹ The resulting anemia is often severe and rapidly progressive, with mortality rates reaching approximately 25% in extravascular cases and up to 75% in intravascular IMHA cases.²

Traditional therapies for IMHA focus on immunosuppressive medications, including corticosteroids, cyclosporine, azathioprine, or mycophenolate mofetil. While these treatments can be life-saving for many patients, they often fail to correct the underlying immune dysfunction leading to frequent relapses, infectious complications, and chronic morbidity. For many dog owners, this leaves few options beyond prolonged illness, drug-related side effects, or euthanasia.²

Mechanisms of IMHA

In healthy dogs, RBCs have a lifespan of ∼100 days, with approximately 600 billion cells produced daily. IMHA disrupts this equilibrium when autoantibodies (typically IgG or IgM) bind to RBC antigens causing rapid hemolysis. In intravascular hemolysis, complement-mediated lysis causes destruction of RBCs within blood vessels. In extravascular IMHA, antibody-tagged RBCs are phagocytosed by splenic or hepatic macrophages, resulting in anemia and the appearance of spherocytes on blood smears.^1,2 Chronic red cell destruction exacerbates systemic inflammation, thromboembolism, and multiorgan dysfunction—especially involving the lungs, liver, and kidneys.

IMHA may be classified as primary (idiopathic) or secondary to an identifiable trigger such as infection, drug exposure, neoplasia, or oxidative injury. Primary IMHA, which lacks an identifiable underlying cause, accounts for approximately 65% of all cases. While secondary IMHA may resolve with the treatment of the inciting condition, primary IMHA often requires long-term immunosuppression. Among these primary cases, 15%–30% are refractory to steroid therapy, representing an estimated 17,355–69,420 dogs per year who may benefit from mesenchymal stem cell (MSC) treatments (Fig. 1).³

FIG. 1.

Flow chart representing the subsets of IMHA incidences in the United States per year. IMHA, immune-mediated hemolytic anemia.

Rationale for stem cell therapy

MSCs have emerged as a promising treatment for autoimmune diseases capable of modulating immune responses without broad immunosuppression. These cells exert therapeutic effects through modulating immune cell activity (paracrine signaling), regulatory T-cell activation, inhibition of proinflammatory cytokines, and restored immune tolerance.⁴ Unlike conventional drugs, MSCs adaptively respond to the local immune environment, reducing the risk of overtreatment or systemic toxicity.

In the context of IMHA, MSC therapy offers a 2-fold benefit: (1) modulation of autoreactive immune responses to halt antibody production by suppression of the immune system’s attack on RBCs and (2) protection of antibody-tagged RBCs from accelerated destruction.⁵ These mechanisms are especially valuable for patients with poor or partial response to immunosuppressive drugs.

Immune tolerance failure

The immune system is a dynamic network of specialized cells designed to protect the body from infections, abnormal cells, and other threats. Among its key players are lymphocytes, which are responsible for recognizing and responding to specific foreign antigens. Their development, selection, activation, and regulation are tightly controlled processes that, when disrupted, can lead to autoimmune diseases such as IMHA.

Immune tolerance re-education

The breakdown of immune tolerance is central to the pathogenesis of IMHA. These mechanistic insights establish a biologically grounded basis for using MSCs in the treatment of IMHA and inform the dosing rationale.

MSCs are responsive cells that exert potent immunomodulatory effects. They secrete transforming growth factor beta (TGF-β) and complement regulatory proteins such as Factor H. TGF-β plays a central role in promoting the development, differentiation, and expansion of regulatory T-cells (Tregs), thereby restoring immune tolerance and preventing inappropriate immune activation that occurs in autoimmune diseases.⁵ Concurrently, MSCs produce Factor H, which inhibits complement activation on RBCs. This helps prevent complement-mediated lysis and protects erythrocytes from destruction.^6,7

Recent studies have further clarified MSC mechanisms, showing that MSCs and the newly minted Tregs they produce act by:

Inhibition of Helper T Cells (TH2): Tregs suppress CD4⁺ TH2 cells, which activate B-cells and promote class switching to IgG—the immunoglobulin subtype most implicated in extravascular hemolysis.

Direct Suppression of B-Cell Proliferation: Tregs can directly inhibit B-cell proliferation and antibody secretion through cell-contact-dependent mechanisms and cytokine-mediated pathways (e.g., interleukin [IL]-10 and TGF-β).

Consumption of IL-2: Tregs express high-affinity IL-2 receptors (CD25) and outcompete effector T-cells for IL-2, reducing T- and B-cell expansion.

Dampening APC Activity: Tregs reduce the costimulatory activity of dendritic cells, leading to diminished antigen presentation and B-cell stimulation.⁸

The therapeutic strategy in this retrospective study mirrors a “vaccination” model for immune re-education. The initial MSC dose was intended to rapidly suppress active RBC destruction through anti-inflammatory and complement-inhibitory actions, while simultaneously initiating Treg recruitment. Subsequent booster doses were designed to reinforce and expand memory T-cell populations, fostering long-term immune tolerance rather than transient suppression.

MSC dosing rationale

A dosing regimen of 2 million cells/kg body weight was employed. This protocol was based on pilot data demonstrating superior clinical efficacy compared with the more traditional 1 million cells/kg standard used in human protocols. The rationale for higher cell dosages included

More robust suppression of complement-mediated RBC destruction.

Stronger and earlier Treg induction.

Enhanced immune recalibration without an increased risk of adverse events.^9,10

Emerging evidence suggests a dose-dependent relationship in MSC therapies, where larger cell numbers promote more robust Treg expansion and longer-lasting immune regulation, particularly in refractory autoimmune diseases.^10,11 Thus, the selection of a 2 million cells/kg dosing protocol was both biologically rational and clinically validated for achieving durable therapeutic success in canine IMHA.

Study objective

This study retrospectively evaluates the clinical efficacy and safety of intravenous allogeneic MSC therapy in dogs diagnosed with IMHA, most of whom exhibited inadequate response to conventional immunosuppressive treatments. A defined core cohort meeting strict inclusion criteria was analyzed to assess MSC dose frequency, hematological recovery, and treatment-related adverse events.

Materials and Methods

Stem cell preparation and quality control

Adipose-derived MSCs were harvested from purpose-screened donor dogs following informed owner consent. Donors were healthy adults screened via complete blood count, serum biochemistry, and infectious disease testing.

MSCs were isolated by enzymatic digestion followed by adherence selection and then expanded to passages 3–6 before cryopreservation. The isolated MSCs were cultured in Dulbecco's modified Eagle medium: Nutrient Mixture F-12 media supplemented with 5% fetal bovine serum and 1% penicillin-streptomycin. Cells were maintained at 37°C, 5% CO₂, and 95% humidity.

Identity was confirmed by flow cytometry (CD73+, CD90+; CD34−, CD45−). Cells were also characterized through induced differentiation with Thermo Fisher’s StemPro differentiation kits. Sterility testing, mycoplasma testing, and viability assays (>85% postthaw) were performed (see supplementary data for further results).

Study design and patient selection

This study was designed as a retrospective, multicenter cohort analysis of 157 client-owned dogs diagnosed with IMHA and treated with allogeneic MSC therapy. Medical records were collected from both general practice and specialty veterinary hospitals between 2019 and 2024. The study sought to evaluate clinical outcomes and treatment safety in actual veterinary settings.

Dogs were eligible for inclusion if they had a confirmed diagnosis of IMHA based on clinical findings, hematological parameters (e.g., regenerative anemia, spherocytosis, autoagglutination, or positive Coombs’s test), and no evidence of secondary causes. All patients received traditional immunosuppressive therapy—corticosteroids alone or in combination with agents such as cyclosporine or mycophenolate mofetil—and many also underwent blood transfusions prior to or during MSC administration. A substantial proportion of patients were refractory to these conventional treatments at the time stem cell therapy was initiated.

For focused outcome analysis, a core cohort of 43 dogs was selected based on:

Confirmed primary IMHA with no significant comorbidities,

Receipt of at least two rounds of MSC therapy,

Availability of complete hematologic follow-up, including serial packed cell volume (PCV) data.

The ages ranged from 10 months to 12 years and 2 months (Table 1). Out of the 43 patients, 61.8% were treated externally at referring hospitals and 38.2% were treated at Safari Veterinary Care Centers.

Table 1.

Accepted Patient Information

Patient name	Age at first round of stem cells	Patient sex
Apollo	6 yr 2 mo	Neutered male
Aurora	3 yr 4 mo	Spayed female
Bear	2 yr 5 mo	Neutered male
Bella R	2 yr	Spayed female
Bella Z	11 yr	Spayed female
Berkley	7 yr	Spayed female
Brady	2 yr	Neutered male
Bulma	1 yr	Intact female
Chaz	1 yr	Neutered male
Coco M	3 yr 7 mo	Spayed female
Coco V	4 yr	Neutered male
Daisy S	7 yr 11 mo	Spayed female
Derp	8 yr	Neutered male
Fiona	4 yr 8 mo	Spayed female
Freddie	7 yr 7 mo	Neutered male
Gerald	10 yr 6 mo	Neutered male
Gus	10 yr	Neutered male
Izzy	2 yr 5 mo	Spayed female
Jax D	5 yr	Neutered male
Jax T	6 yr 8 mo	Neutered male
Jetty	12 yr	Spayed female
Josey	6 yr	Spayed female
Josie	8 yr	Spayed female
June	5 yr	Spayed female
Kali	7 yr 9 mo	Intact female
Lady	8 yr	Spayed female
Little Bear	3 yr 9 mo	Neutered male
Lizzy	12 yr	Spayed female
Lola K	7 yr 2 mo	Spayed female
Luna C	5 yr 8 mo	Intact female
Luna L	8 yr	Spayed female
Milhouse	5 yr	Neutered male
Molly	10 yr 8 mo	Spayed female
Nike	5 yr	Spayed female
Parker	3 yr 6 mo	Neutered male
Pearl	7 yr	Spayed female
Princess	12 yr 2 mo	Spayed female
Robin	3 yr	Intact female
Rocky	10 mo	Intact male
Sage	5 yr 6 mo	Spayed female
Stun	11 yr 9 mo	Neutered male
Tomac	2 yr 2 mo	Intact male
Wednesday	5 yr 11 mo	Spayed female

mo, month; yr, year.

MSC therapy protocol

Each dog received MSCs intravenously at a standardized dose of 2 million cells/kg body weight. Doses were either administered directly at Safari Veterinary Care Centers or shipped overnight to external hospitals for next-day use. No pretreatment antihistamines or corticosteroids were routinely administered unless directed by the attending clinician.

Ethical approval and informed consent

This study was conducted at Safari Veterinary Care Centers, a private veterinary hospital. As the study involved clinical treatment of client-owned dogs with allogenic MSCs, formal Institutional Animal Care and Use Committee approval was not applicable. All treatments were performed with the informed, written consent of each pet owner, following a detailed discussion of the procedure, potential risks, and benefits. All procedures adhered to the ethical standards of the American Veterinary Medical Association and applicable veterinary regulations.

Results

Outcome measures

Medical records were reviewed for baseline PCV, immunosuppressive treatment history, MSC administration dates and doses, and follow-up PCV outcomes. The primary efficacy endpoint was defined as achieving a post-treatment PCV ≥30%, a threshold consistent with established veterinary consensus on meaningful hematological recovery in IMHA.^12
–14 Restoration of PCV to at least 30% indicates sufficient RBC mass to support systemic tissue oxygenation, stabilize cardiovascular function, and reduce the clinical risks associated with severe anemia, such as hypoxia and organ injury. Sustained PCV above 30% has been shown to predict improved survival rates and lower relapse risk in dogs with IMHA.¹³

Therapeutic success, defined as achieving a post-treatment PCV ≥30%, was observed in 33 of the 43 dogs (76.7%) in the core analysis cohort—patients with primary IMHA who received two to three rounds of MSC therapy and met all inclusion criteria.

In the broader cohort of 157 dogs treated with MSCs, 35 were excluded due to insufficient hematological data (e.g., missing PCV values or platelet-only records). Among the remaining 122 dogs, 27 died or were euthanized before the evaluation of treatment response could be conducted, leaving 95 evaluable cases. Of these, 68 dogs achieved a PCV ≥30%, yielding a therapeutic success rate of 72% in the more inclusive population, which encompassed dogs with comorbidities and those who received only a single MSC dose. This highlights the potential benefits of MSC therapy even outside the core analysis cohort.

Comparative analysis of hematological response showed that dogs treated with MSCs experienced a mean PCV increase of 23.4 points (±3.05; 95% confidence interval [CI]), whereas dogs receiving only traditional therapy exhibited a significantly lower mean increase of 3.84 points (±2.47; 95% CI). This represents approximately a 6-fold greater hematological improvement associated with MSC treatment (Fig. 2).

FIG. 2.

Increase in PCV after MSC therapy versus traditional treatments. MSC, mesenchymal stem cell; PCV, packed cell volume.

Number of MSC rounds

Most dogs in the study received two rounds of MSC therapy, with 68.9% (20/29) achieving a post-treatment PCV ≥30% and an average PCV increase of 23.5 points, the highest observed among all dosing groups. Dogs receiving three rounds also responded well, with a 77.8% success rate (7/9) and a mean PCV increase of 23.2 points. A small number of outliers received five or more rounds, but due to limited sample size, these were excluded from comparative analysis (Table 2).

Table 2.

Number of IV MSC Rounds and Their Success Rates

Number of rounds	Successes (PCV ≥30%)	Total cases	Success rate (%)
2	20	29	68.90
3	7	9	77.80
4	5	5	100
5	1	1	100
8	1	1	100

MSC, mesenchymal stem cell; PCV, packed cell volume.

Due to only one patient having either five or eight rounds, they were not considered statistically significant.

Treatment consistency was evident across clinical settings. Comparable success rates were observed between dogs treated on-site at Safari Veterinary Care Centers and those managed externally using overnight-shipped allogeneic MSC doses.

Safety assessment

Adverse reactions were identified through retrospective review of clinical notes. Among the 157 dogs treated with stem cell therapy for IMHA, 9 dogs (5.7%) experienced one or more adverse events. Eighteen adverse event instances were documented across these nine dogs, including symptoms such as fever, collapse, diarrhea, and transient seizure activity. No serious adverse events or deaths were observed or attributed to MSC therapy. All adverse events were mild to moderate in severity and resolved with supportive care. Deaths attributable to underlying IMHA severity were not classified as treatment-related adverse events.

Discussion

Administration of MSCs was associated with meaningful clinical improvement and a favorable safety. MSC treatment resulted in substantially greater increases in PCV and higher rates of therapeutic success. The consistency of outcomes across multiple hospital settings—both internal and external—supports the potential utility of MSC therapy as an effective adjunct in the management of canine IMHA.

The primary aim of this case series was to investigate the effectiveness of MSC therapy in the treatment of IMHA in dogs, with a specific focus on achieving immune modulation and restoring immune tolerance.¹⁵ The results indicate a notable rate of successful outcomes among the treated dogs. This outcome is particularly encouraging, suggesting that MSC therapy can serve as a valuable intervention in managing IMHA, especially when conventional treatments have proven inadequate.¹⁶ This study demonstrates that intravenous administration of allogeneic MSCs is a clinically effective and safe strategy for canine IMHA management.

Durable immune modulation

MSC therapy offers a targeted intervention that addresses the cause of IMHA as failure of immune tolerance rather than broadly suppressing immunity. Unlike drugs that suppress immunity, MSCs recalibrate it. They promote Tregs and suppress complement, addressing IMHA at its root. These effects may reduce relapse rates and long-term drug dependence. This results in durable remissions without the side effect profile of long-term immunosuppression^17,18 Moreover, the therapeutic effects of MSCs extend beyond mere symptom management; they facilitate a restoration of immune homeostasis.¹⁹ This immune-modulating capacity is crucial in treating autoimmune diseases where preventing relapses and decreasing the necessity for continuous immunosuppressive medications are major clinical challenges.²⁰ Our data, combined with supportive evidence, strongly support the use of MSCs as a novel treatment strategy for IMHA in dogs.

Dose response and clinical implications

The observed correlation between the number of MSC therapy rounds and the improvement in PCV levels highlights the importance of treatment consistency. Specifically, two to three rounds of MSC therapy were associated with the most significant enhancements in PCV, suggesting that repeated exposure to MSCs may be necessary to achieve a sustained therapeutic effect. This repeated exposure may foster long-term remission by promoting regulatory and memory T-cell populations and more permanent immune tolerance mechanisms.²¹

The administration of two to three rounds further confirmed that the “vaccination” model of administration is effective in this case. It is hypothesized that the first round of stem cells given is to mitigate the acute destruction of RBCs through anti-inflammatory paracrine factors.²² The destruction of RBCs may also be mitigated through the inhibition of the complement system against RBCs. Stem cells have been shown to secrete Factor H, which acts as a protective barrier against complement activation.²³ The second to third “booster” rounds of MSC therapy are then able to restore immune tolerance. Further exploration into the specific mechanisms driving this response is warranted, potentially uncovering insights into ideal treatment intervals and dosing strategies.

Treatment scalability and safety profile

Importantly, shipment of cells resulted in MSC therapy that was consistent across clinical settings, reinforcing the broader scalability and accessibility of this approach—a critical consideration for broader clinical adoption.

The study protocol provided a standardized framework for dosing (2 million cells/kg) and administration, minimizing variability. The low incidence of adverse events, predominantly mild infusion reactions, and no treatment-related deaths suggests that MSC therapy can be safely integrated into IMHA treatment protocols. Overall, the safety profile of MSC therapy, combined with its potential for immune modulation and restoration of immune tolerance, positions it as a promising treatment modality for IMHA in dogs.

Future directions

Several future directions are essential to advancing the clinical adoption of MSC therapy for IMHA. First, randomized controlled trials are needed to validate these outcomes in a statistically rigorous framework and account for confounding variables. Comparative investigations should also evaluate MSC therapy as an adjunct to conventional immunosuppressants, potentially identifying synergistic regimens that reduce the need for chronic pharmaceutical intervention.

Beyond IMHA, there is strong rationale to expand the application of MSC therapy to other autoimmune conditions including immune-mediated thrombocytopenia, Evan’s syndrome, and inflammatory bowel disease. Such studies will help define disease-specific protocols and broaden the therapeutic scope of MSCs in veterinary medicine.

Equally important is the standardization of cell manufacturing practices. As regulatory scrutiny increases, harmonizing MSC production under current good manufacturing practice standards will be critical for FDA Center for Veterinary Medicine recognition and eventual product licensing. Safari stem cell’s current protocols, including rigorous donor screening, validated cryopreservation, and consistent cold-chain logistics, lay the groundwork for this transition. The end goal is to bring these technologies to the private practitioner.

Conclusion

Intravenous allogeneic MSC therapy restores immune tolerance, improves hematological outcomes in canine IMHA, and has a strong safety profile. By promoting the recruitment and expansion of regulatory T-cells, inhibiting complement activation, and reducing the inflammatory destruction of RBCs, MSCs target the immunological cause of IMHA. This represents a meaningful shift from traditional generalized immune suppression toward targeted immune recalibration. Moreover, the therapy’s ability to be shipped without loss of efficacy supports clinical feasibility of this approach, marking an advancement in the accessibility of regenerative treatments. These findings support MSC therapy as an adjunctive treatment for canine IMHA and lay the foundation for adoption in veterinary regenerative medicine.

Footnotes

Acknowledgments

The following individuals associated with Safari Stem Cell and Safari Veterinary Care Centers were contributors to this project: Seymone Batiste, Melinda Wharton, Michael McCord, Susan Mooney, and Lori McCord.

Author Disclosure Statement

The authors were both affiliated with Safari Veterinary Care Centers at the time of the study.

Funding Information

No funding was received for this article.

Supplementary Material

Supplementary Figure S1

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Supplementary Material

Please find the following supplemental material available below.

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Intravenous Allogeneic Mesenchymal Stem Cell Therapy for Canine Immune-Mediated Hemolytic Anemia: A Retrospective Clinical Evaluation

Abstract

Introduction

Background and clinical challenge

Mechanisms of IMHA

Rationale for stem cell therapy

Immune tolerance failure

Immune tolerance re-education

MSC dosing rationale

Study objective

Materials and Methods

Stem cell preparation and quality control

Study design and patient selection

MSC therapy protocol

Ethical approval and informed consent

Results

Outcome measures

Number of MSC rounds

Safety assessment

Discussion

Durable immune modulation

Dose response and clinical implications

Treatment scalability and safety profile

Future directions

Conclusion

Footnotes

Acknowledgments

Author Disclosure Statement

Funding Information

Supplementary Material

References

Supplementary Material