Abstract
Purpose of Review:
Significant advancements have been made in the field of vascularized composite allotransplantation (VCA); however, like solid organ transplantation, bypassing the recipient’s immune response remains a significant obstacle to long-term allograft survival. Therefore, strategies to overcome acute and chronic rejection and minimize immunosuppressive therapy are crucial for the future of VCA. This review highlights recent attempts to induce tolerance in VCA and discusses key findings through a clinical lens.
Recent Findings:
Promising VCA tolerance protocols are being investigated, with five recent studies illustrating various successes. These preclinical approaches demonstrate a correlation between the presence of donor-derived T-cells and VCA tolerance, the importance of using clinically available reagents within preclinical protocols, and the ability to induce sustained tolerance through non-myeloablative methods. Furthermore, environmental factors, such as NB-UVB light are being investigated for their immunomodulation properties and may influence VCA graft rejection.
Summary:
To widen the scope of VCA, minimization of immunosuppression is needed. Overall, tolerance induction protocols should have a low-toxicity level, minimally invasive induction therapies, and utilize short-term immunosuppressive medications. By examining the milestones of recent studies, researchers can gain new technical approaches to immune modulation and make data-driven amendments to tolerance protocols in preparation for clinical translation.
Keywords: Vascularized composite allotransplantation, Immune tolerance
Introduction
While vascularized composite allotransplantation (VCA) serves as a validated reconstructive option with promising functional and aesthetic outcomes1,2, the inherent adverse effects of maintenance triple immunotherapy (tacrolimus, mycophenolate mofetil, and corticosteroids) can be severe and decrease patient life expectancy3. Immunotherapy is successful at preventing allograft loss; however, acute rejection episodes within the skin, a common component of VCA grafts, still occur4. Due to this risk, VCA recipients are selected based on a demonstrated ability to comply with an immunotherapy regimen and attend close follow-up visits. Therefore, to improve patient outcomes of this restorative surgery and serve a broader patient population, methods of inducing immunological tolerance and homeostasis must be developed and implemented. Tolerance would prevent any destructive immunological response to the antigens present in the VCA tissue, allowing for long-term graft survival in the setting of no immunosuppressive therapy. It can be achieved centrally, through the deletion or inactivation of maturing intrathymic alloreactive T cells, or peripherally, through the deletion, inactivation, or regulation of alloreactive T cells within the circulation5. In the present article, we review recent VCA immune tolerance induction methods to provide novel concepts for the development of a protocol that can be translated from bench to bedside.
Methods
A PubMed, Embase, and Google Scholar search was conducted using the following search terms: “vascularized composite allotransplantation”, “composite tissue allotransplantation”, “immune tolerance”, “tolerance induction”, “immunomodulation”, and “chimerism”. Inclusion criteria consisted of articles, published since 2022, describing tolerance induction methods within animal and human studies of VCA. Articles that did not describe tolerance induction techniques in VCA, did not investigate tolerance as a long-term outcome, described in-vitro studies, reviewed previously described studies, or were written in a language other than English were excluded. In total, 5 articles were reviewed.
Tolerance Induction: Swine Studies
Preclinical animal models are essential for both understanding and achieving immune tolerance in VCA. When studying immunological responses to myocutaneous VCA grafts, pig skin in particular, offers a platform that is structurally, cellularly, and antigenically similar to humans6. In addition, MHC-defined pigs are available allowing for control of the degree of MHC mismatch. Recently, Lellouch et al. demonstrated VCA tolerance in a clinically relevant large animal model across class I MHC barriers8. This study matched donor and recipient MGH miniature swine for class II swine leukocyte antigen (SLA), meanwhile mismatching each pair for class I SLA. Osteomyocutaneous VCAs, including the distal femur and proximal tibia, were performed in seven pigs, with two pigs serving as controls that did not undergo induction therapy (Table 1). Lellouch et al. applied a mixed chimerism protocol that included irradiation conditioning, bone marrow transplantation, and a short course of maintenance immunosuppression to five pigs (Table 1).
Table 1:
Description of tolerance induction protocol, VCA model, and immunological outcomes in a swine VCA study.
| Study | Experimental Group | Induction Phase (POD) | VCA Model (POD) | Maintenance Phase (POD) |
Immuno-suppression withdrawal (POD) |
Graft Survival (Days) | VCA Tolerance |
|---|---|---|---|---|---|---|---|
| Lellouch et al. | Pigs 1, 2 | TBI 300 cGy (−2) + TI 700 cGy (−2) | Osteo-Myocutaneous Allograft to the Abdomen + Donor BM IV Infusion (0) | CTLA4-Ig (0, 2, 4, 6) + FK506 (0–45) | ** | ** | ** |
| Pigs 3, 4, 5 | TBI 300 cGy (−2) + TI 700 cGy (−2) + Medrol (−2, −1, 0) | CTLA4-Ig (0, 2, 4, 6) + FK506 (0–45) + Anti-IL6R mAb (0, 7, 14, 21, 28) | 45 | 400 | Yes | ||
| Pigs 6, 7 | -- | Osteo-Myocutaneous Allograft to the Abdomen | -- | -- | 11 | No |
TBI; Total Body Irradiation, cGy; Centigray, TI; Thymus Irradiation, Medrol; Methylprednisolone, BM; Bone Marrow, CTLA4-Ig; Belatacept, FK506; Tacrolimus, Anti-IL6R mAb; Tociluzimab, POD; Postoperative Day, IV; Intravenous.
Outcome not evaluated due to early removal of pigs from the study.
Lellouch et al. found that the control VCA recipients experienced early graft rejection by POD 11. In contrast, pigs 3, 4, and 5 (60%), who were treated with additional methylprednisolone preoperatively and Tocilizumab postoperatively, demonstrated long-term allograft survival following the discontinuation of immunosuppression on postoperative day (POD) 45. Interestingly, pigs 1 and 2 did not receive these additional medications and experienced early idiopathic pulmonary syndrome following the standard mixed chimerism protocol. The conditioning protocol (300 cGy total body irradiation and 700 cGy thymic irradiation), may have contributed to the development of irradiation-induced pulmonary distress and through blocking IL-6, with the addition of Tocilizumab, this adverse effect was prevented. Pigs 3, 4, and 5 also displayed multilineage mixed hematopoietic chimerism, as indicated by a >80% replacement of recipient myeloid cells and 30–60% replacement of B and T cell populations by donor cells. Furthermore, representative sub-analyses of T cells revealed that the percent of donor and recipient T cells equalized around POD 100 and continued this trend until the end of the study. This data, in combination with a lack of graft rejection or graft vs host disease (GVHD) following immunosuppression withdrawal, supports the use of preoperative steroids and postoperative Tocilizumab in VCA tolerance induction protocols using irradiation. Although the addition of these medications proved beneficial, developing protocols that avoid the toxicity of irradiation would be more ideal for the clinic.
Lellouch et al. mention, “all conditioning medications employed in this study are FDA-approved for clinical use7”, which serves as an advantage for future translation of this protocol to the clinic. Including additional laboratory tests to monitor for acute kidney injury, dyslipidemia, neutropenia, thrombocytopenia, and abnormal liver enzymes, would provide data to strengthen the clinical applicability of this protocol, as these are potential side effects of both FK506 and Tocilizumab8,9. Furthermore, understanding the systemic effects of the medications used in a tolerance protocol would allow for precise alterations in their target levels, so that researchers can induce a successful state of immune tolerance without causing additional morbidity. It is also unclear how achieving tolerance across a class-I MHC barrier can be successfully translated to the clinic, as it is difficult and impractical to match class-II between each VCA donor and recipient. When developing protocols for clinical VCA, which utilizes allografts acquired from deceased donors, that are likely to be fully MHC mismatched, it is crucial to test these approaches on comparable tissue.
Starting on POD 7, a substantial expansion of donor-derived CD4−CD8− T-cells, producing IL-10 cytokine, was observed. These cells approached equilibrium with that of recipient T-cells, at POD 85. Interestingly, a recent study found that in the setting of no immunosuppression, fully MHC-mismatched murine facial allografts treated with local injections of IL-10 modified mRNA had a significantly prolonged survival rate secondary to increased regulatory T-cells (Tregs) and donor Treg chimerism10. In contrast, Lellouch et al. did not observe an expansion of FOXP3+ Tregs in the long-term tolerant pigs. Interestingly, FK506 impairs Tregs by inhibiting Treg activation, production, and the transcription nuclear factor of activated T-cells required for IL-2 transcription11. Considering that IL-2 is essential for Treg development, homeostasis, and function12, maintenance therapy with intravenous FK506 for 45 days may have affected Treg production. Furthermore, the authors did not histologically analyze the allograft tissue. It has been found that Tregs migrate to and enrich human skin allografts to control alloresponses13. Therefore, it is possible that the lack of Treg expansion demonstrated in this model is a reflection of Treg relocation to the allograft tissue. Also, Tregs suppress effector T-cell activation, thus preventing the downstream stimulation of B cells to produce allo-antibodies14. This may explain the consistent lack of donor-specific antibodies, at any given time point, during this 400-day study. Future studies conducting immunohistochemistry analysis of periodic graft biopsies will be able to better localize and quantify the Treg population during a state of immune tolerance.
Tolerance Induction: Rodent Studies
Insights obtained from preclinical rat VCA models have informed novel tolerance induction protocols that use strategies such as mixed chimerism, Treg therapy, and co-stimulation blockade. Recently, Lin et al. utilized a combination of vascularized bone marrow (VBM) transplantation and mystacial pad transplantation (partial non-bone-containing face graft) to induce and maintain donor-specific tolerance15. In this study, there were five VBM and three mystacial pad transplantation groups (Table 2). The authors found that a combination of pre- and post-operative anti-lymphocyte serum (ALS) and a short maintenance therapy of tacrolimus and rapamycin (RPM) significantly prolonged VBM allograft survival (>120 days). Moreover, mixed chimerism was detected on POD 30 for group 5 (>12% donor lymphoid cells, and >10% donor myeloid cells) along with a statistically significant lower percentage of both CD8+ (<5%) and CD4+ T-cells (<5%) and a higher percentage of protective CD25+FoxP3+ Tregs (>14%) when compared to groups 1–4.
Table 2:
Immunological outcomes and animal characteristics of an immune tolerance protocol in a rat VCA model.
| Study | Species | Experimental Group (n=) | Induction Phase (POD) | VCA Model (POD) |
Maintenance Phase (POD) |
Graft Survival (Days) | VCA Tolerance |
|---|---|---|---|---|---|---|---|
| Lin et al. | Rats | 1 (3) | -- | VBMT BN → BN |
-- | >120 days | -- |
| 2 (3) | ALS 1 cc (−3, 1) |
VBMT BN → LEW |
-- | 15 | No | ||
| 3 (3) | -- | VBMT BN → LEW |
Tac 2 mg/kg/day (0–7) + RPM 3 mg/kg/day (7–28) | 25 | No | ||
| 4 (5) | ALS 1 cc (−3, 1) |
VBMT BN → LEW |
Tac 2 mg/kg/day (0–7) | >120 days* | No | ||
| 5 (5) | VBMT BN → LEW |
Tac 2 mg/kg/day (0–7) + RPM 3 mg/kg/day (7–28) | >120 days | Yes | |||
| 6 (3) | -- | MPT BN → BN |
-- | >90 days | -- | ||
| 7 (6) | ALS 1 cc (−3, 1) |
MPT BN → LEW |
Tac 2 mg/kg/day (0–7) + RPM 3 mg/kg/day (7–28) | 65 | No | ||
| 8 (6) | VMBT + MPT (28) BN → LEW |
Tac 2 mg/kg/day (0–7 and 28–35) + RPM 3 mg/kg/day (7–28) | >90 days | Yes |
ALS; Antilymphocyte Serum, VBMT; Vascularized Bone Marrow Transplant (hind limb), MPT; Mystacial Pad Transplant, Tac; Tacrolimus, RPM; rapamycin.
At this time, the graft only demonstrated 50% survival.
Furthermore, donor skin grafts engrafted to the tolerant VBM allograft recipients survived indefinitely, while third-party skin grafts were rejected by POD 6. This highlights the ability of VBM transplantation to reduce the need for long-term immunosuppressants, however, to make this protocol more clinically relevant, methods to transplant donor derived hematopoietic stem cell niches separate from the bone tissue should be explored.
For the mystacial pad transplantation groups (7 and 8), the circulating CD4+ and CD8+ T cells, Treg, and natural killer cells were not significantly different at POD 30. Although, group 8 demonstrated significantly prolonged allograft survival when compared to group 7 (>90 vs. 65 days). Interestingly, for group 8 the percentage of donor cells circulating in the recipient steadily decreased in the postoperative period, until the level nearly equalized with that of the syngeneic model, group 6, at 0% on POD 90. This steady decline in mixed chimerism raises questions about the sustainability of graft tolerance using this model. While tolerance has been achieved by induction of either transient mixed chimerism or persistent full donor chimerism16, graft rejection secondary to retained recipient immune-effector mechanisms is a possible complication of loss of donor chimerism17. Therefore, clinical considerations for this protocol include the potential use of post-transplant donor lymphocyte infusion to increase donor chimerism and prolong donor-specific tolerance within the VCA graft recipients18.
Cheng et al. recently investigated a tolerogenic protocol in Lewis (LEW) and Brown Norway (BN) rat donor-recipient pairs and Balb/C and C57BL/6 mice donor-recipient pairs using a heterotopic hindlimb model19. They conducted 26 VCAs in rats and 38 in mice (Table 3). The authors demonstrated that an effective tolerogenic regimen for one donor-recipient combination will not necessarily elicit similar outcomes in the reciprocal combination. For example, in LEW rats, one ALS dose and 10 days of cyclosporine A (CsA) maintained around 5% donor cell presence in the peripheral blood until POD 30. However, this regimen did not suffice to maintain chimerism in BN rats by POD 22 and therefore CsA treatment was extended to 21 days to sustain chimerism. Furthermore, BN recipients treated with two doses of ALS followed by CsA showed a decline to 40% native lymphocytes and monocytes by POD 11, while LEW recipients experienced a dramatic decline to 20%, after only one ALS dose and CsA.
Table 3:
Description of a rat VCA model and immune tolerance protocol outcomes.
| Study | Species | Experimental Group (n=) | Induction Phase (POD) | VCA Model (POD) |
Maintenance Phase (POD) |
Graft Survival (Days) | VCA Tolerance |
|---|---|---|---|---|---|---|---|
| Cheng et al. | Rats | 1 (3) | -- | Hindlimb Transplant LEW → BN |
-- | 7 ± 0.8 | No |
| 2 (3) | ALS 0.5 mL (1) | CsA 16 mg/kg (0–10) |
23 ± 2.5 | No | |||
| 3 (4) | ALS 0.5 mL (1) + BN ADSCs 2 × 106 (1) |
28 ± 2.5 | No | ||||
| 4 (4) | ALS 0.5 mL (−3,1) |
29 ± 2.2 | No | ||||
| 5 (4) | ALS 0.5 mL (−3,1) + BN ADSCs 2 × 106 (1) |
27 ± 5.5 | No | ||||
| 6 (4) | ALS 0.5 mL (−3,1) |
CsA 16 mg/kg (0–21) |
43 ± 56 | Yes* | |||
| 7 (4) | ALS 0.5 mL (−3,1) + BN ADSCs 2 × 106 (1) |
39 ± 43 | Yes* | ||||
| 2L (5) | ALS 0.5 mL (1) | Hindlimb Transplant BN → LEW |
CsA 16 mg/kg (0–10) |
55 | No | ||
| 3L (6) | ALS 0.5 mL (1) + LEW ADSCs 2 × 106 (1) | 150 | Yes | ||||
| Mice | 1 (4) | -- | Hindlimb Transplant C57BL/6 → C57BL/6 | -- | >120 | -- | |
| 2 (4) | -- | Hindlimb Transplant BALB/c → C57BL/6 | -- | 10 | -- | ||
| 3 (15) | Anti-CD154 1 mg (0) |
CTLA4-Ig 0.5 mg (2), RPM 3 mg/kg/day (0–7), RPM 3 mg/kg Q.O.D (8–28) | >120 | Yes | |||
| 4 (15) | Anti-CD154 1 mg (0) |
Hindlimb Transplant C57BL/6 → BALB/c | CTLA4-Ig 0.5 mg (2), RPM 3 mg/kg/day (0–7), RPM 3 mg/kg Q.O.D (8–28) | >120 | Yes |
ALS; Antilymphocyte Serum, RPM; rapamycin, CTLA4-Ig; Cytotoxic T lymphocyte-associated protein-4 immunoglobulin, CsA; Cyclosporine A, ADSCs; Adipose-Derived Stem Cells, BN; Brown Norway Rat, LEW; Lewis Rat, POD; Postoperative Day, Q.O.D; Every Other Day.
One recipient from each of these groups demonstrated induced donor-specific tolerance.
This disparity suggests that BN rats may respond less effectively to ALS treatment and/or their cells may repopulate sooner after depletion. Nonetheless, these findings highlight the importance of utilizing reciprocal pairing in immune tolerance protocols to allow for the identification of immune cell responses to treatments within different strains and to validate the widespread efficacy of the protocol. The mice findings paralleled those of the rats, as the BALB/c strain showed poorer overall survival and exhibited lower chimerism levels when compared to the C57BL/6 strain. In addition, for both strains, achieving tolerance after 4 months was positively correlated with higher chimerism levels measured at POD 30. This underscores the importance of monitoring multilineage chimerism levels to obtain information about the engraftment process and provide early intervention if needed.
Similar to the previous study, Zhang et al. have applied efforts to induce mixed chimerism via non-myeloablative recipient conditioning in rodent models20. This study had eight rat and five mice experimental groups (Table 4), using either BN or green fluorescent protein Sprague-Dawley (gfp-SD) rat donors into LEW rat recipients and BALB/c nude mice into B6 SCID mice recipients as well as B10.A mice into B6 recipients. The authors conducted vascularized skin/muscle (VSM) flap transplants with or without donor bone marrow cell transfusion (BMC), osteomyocutaneous (distal ½ of the femur bone) vascularized skin/muscle/bone (VSMB) flap transplants, and complete hindlimb transplants. In the BN rat to LEW rat VCA cohort, both the VSM or VSM+BMC recipients exhibited transient, low-level donor cell chimerism that decreased during the 2–6 weeks following transplantation. Meanwhile, the VSMB and hindlimb recipients maintained stable mixed chimerism up to 24 weeks post-transplant. Similarly, in the gfp-SD rat to LEW rat VCA cohort, donor cell chimerism persisted for over 24 weeks in both the VSMB and hindlimb recipients, while only 0.5–1% of donor cells were detected in either VSM or VSMB+BMC recipients during the 2–8 weeks post-transplant.
Table 4:
Description of a tolerance induction study using rodents.
| Study | Species | Experimental Group (n=) | Induction Phase (POD) | VCA Model (POD) |
Maintenance Phase (POD) |
Graft Survival (Days) | VCA Tolerance |
|---|---|---|---|---|---|---|---|
| Zhang et al. | Rats | 1 (6) | ALS 0.5 mL (−4, 1) |
VSM Transplant BN → LEW |
CsA 0.6 mg/kg (0–6) + RPM 0.5 mg/kg (7–20) |
39 | No |
| 2 (6) | VSM + BMC Transplant BN → LEW |
70 ± 10 | No | ||||
| 3 (6) | VSMB Transplant BN → LEW |
100 ± 12 | Yes | ||||
| 4 (10) | Hindlimb Transplant BN → LEW |
>120 | Yes | ||||
| 5 (4) | VSM Transplant gfp-SD → LEW |
47 | No | ||||
| 6 (4) | VSM + BMC Transplant gfp-SD → LEW |
71.5 | No | ||||
| 7 (8) | VSMB Transplant gfp-SD → LEW |
>120 | Yes | ||||
| 8 (6) | Hindlimb Transplant gfp-SD → LEW |
>120 | Yes | ||||
| Mice | 1 (4) | -- | VSM + BMC Transplant BALB/c nude → B6.SCID |
-- | -- | -- | |
| 2 (4) | -- | VSMB Transplant BALB/c nude → B6.SCID |
-- | -- | -- | ||
| 3 (4) | -- | Hindlimb Transplant B10.A → B6 |
-- | 10.5 | No | ||
| 4 (6) | Anti-CD40L mAb 0.5 mg (0) | VSM Transplant B10.A → B6 |
CTLA4/Fc 0.5 mg (2) + RPM 3 mg/kg/day (0–6) + RPM 3 mg/kg Q.O.D (7–27) | 44 | No | ||
| 5 (6) | Hindlimb Transplant B10.A → B6 |
>140 | Yes |
ALS; Antilymphocyte Serum, RPM; rapamycin, CsA; Cyclosporine A, BN; Brown Norway Rat, LEW; Lewis Rat, VSM; Vascularized Skin/Muscle Flap, VSMB; Vascularized Skin/Muscle/Bone Flap, BMC; Bone Marrow cells, gfp-SD; green fluorescent protein Sprague-Dawley, CTLA4/Fc; Cytotoxic T lymphocyte-associated protein-4, Anti-CD40L mAb; Frexalimab, POD; Postoperative Day, Q.O.D; Every Other Day.
Furthermore, when the donor bone component of the VCA was removed from the VSMB gfp-SD recipients at POD 7, they found that the level of donor chimerism dropped rapidly to around 0% within 6 weeks, leading to rejection of the residual VSM flap. However, when the bone component was removed at 2-, 4-, and 20-weeks post-transplant, the chimerism level decreased to 1–2% within 1 week but quickly increased to 6–12% and persisted at 4.5–5.5% for >24 weeks for 60% of recipients. Considering the significant role that donor derived hematopoietic stem cell niches play in inducing and maintaining mixed chimerism following VCA, future tolerance protocols should be geared toward including these cells. However, GVHD is a frequent complication of allogeneic bone marrow transplantation, and steps should be taken to minimize the risk of this adverse side effect.
Lastly, the authors detected a specific deletion of alloreactive T-cell clones in the blood of the B6 nude mice who had received a chimeric thymus from immune tolerant B6 mice. This deletion may be the reason why the nude mice bearing a tolerant chimeric thymus demonstrated prolonged engraftment of donor-specific B10.A skin grafts, with 50% of them surviving indefinitely (>120 days). This data emphasizes the role of the thymus in chimerism-mediated central tolerance and offers new considerations for future tolerance induction protocols.
Huang et al. recently investigated the effect of narrow-band ultraviolet B (NB-UVB) irradiation, a known immunomodulator, on donor cell chimerism following a heterotopic hindlimb transplant in a rat model21. This study included five experimental groups (Table 5). Allogenic transplants were performed using BN rat donors into LEW rat recipients. This study found that despite the use of immunosuppressants, allograft rejection was increased by postoperative NB-UVB irradiation to the VCA graft skin. Group 4, the cohort that received ALS induction therapy and tacrolimus maintenance therapy without NB-UVB exposure, was the only group, besides the syngeneic group, to demonstrate graft acceptance.
Table 5:
Rodent VCA study description.
| Study | Species | Experimental Group (n=) | Induction Phase (POD) | VCA Model (POD) |
Maintenance Phase (POD) |
Graft Survival (Days) | VCA Tolerance |
|---|---|---|---|---|---|---|---|
| Huang et al. | Rat | 1 (4) | -- | Hindlimb Transplant BN → BN |
-- | 30┼ | -- |
| 2 (4) | -- | Hindlimb Transplant BN → LEW |
-- | 7.5 | No | ||
| 3 (4) | -- | NB-UVB 1350 mJ/cm2 x3/wk (1–30) |
8.5 | No | |||
| 4 (5) | ALS 1 mL (−3,1) |
Tac 1 mg/kg/day (0–7) |
30┼ | Yes | |||
| 5 (5) | ALS 1 mL (−3,1) |
Tac 1 mg/kg/day (0–7) + NB-UVB 1350 mJ/cm2 ×3/wk (1–30) |
26 | No |
ALS; Antilymphocyte Serum, Tac; Tacrolimus, NB-UVB; Narrow-band Ultraviolet B Irradiation.
The study ended at this time.
In contrast, the groups exposed to NB-UVB (3 and 5), had a mean survival of 8.5 and 26 days, respectively. Furthermore, NB-UVB was shown to decrease multilineage chimerism, with group 5 demonstrating significantly lower levels of chimerism in both the graft-accepted and graft-rejected recipients when compared to group 4 (0.25% ± 0.24% and 0.36% ± 0.18% for donor lymphocytes, respectively). Notably, when comparing the group 5 recipients that rejected the allograft to group 4 recipients that did not, the percentage of CD8+ T cells increased (16.3% ± 5.1% vs 7.4% ± 1.0%, respectively), and the percentage of protective Tregs decreased (4.1% ± 0.9% vs 1.6% ± 0.3%, respectively). While additional research is required to determine the precise NB-UVB dosage needed for effective immunosuppression, particularly with a larger sample size and extended observational period, this study highlights the potential harm that NB-UVB exposure can inflict on the skin component of VCA grafts. Researchers should consider the possible influence of environmental factors on the development and maintenance of immune tolerance and strategize ways to reduce VCA graft exposure.
Conclusion
Insights gleaned from the studies included in this review provide a foundation for developing new strategies to induce and monitor tolerance in VCA. Overall, a successful tolerance induction protocol should have a low toxicity level, require minimal induction therapy, and utilize short-term immunosuppressive medications. Researchers are encouraged to continue exploring novel immunomodulatory approaches, with the overall goal of translating their findings to the clinic.
Key Points.
Success of immune tolerance protocols across fully mismatched barriers will make them more clinically relevant.
Reciprocal pairing in immune tolerance protocols allows for the identification of specific donor/recipient immune cell responses and validation of the protocol’s efficacy.
Monitoring multilineage chimerism levels will allow for preemptive strategies to enhance VCA results by intervening before rejection occurs.
VCA immune tolerance protocols should minimize the use of toxic conditioning approaches such as irradiation of the host and myeloablative therapies.
Future tolerance protocols should consider the impact of environmental exposures on the immunological responses of VCA grafts.
Financial support and sponsorship:
This work was supported by the NIH/NCATS Colorado CTSA Grant Number T32 TR004367 and UM1 TR004399. Contents are the authors’ sole responsibility and do not necessarily represent official NIH views.
Footnotes
Conflicts of interest: None
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