Immunomodulating drugs include immunostimulating agents and immunosuppressants. The term immunosuppressant covers a range of agents that interfere with the body’s immune system in different ways such that the immune response of the body is reduced to some degree, or even blocked. The most prominent conditions in need of immunosuppressant medications are autoimmune disorders and hypersensitivities (allergies), and the need to suppress organ rejection after allotransplantation of tissues or organs (transplantation from a genetically non-identical donor). A more recent addition of conditions treated with immunosuppressants are those due to adverse effects of immunotherapies, immune-related adverse effects (IREAs) in these treatments of some malignancies.

Immunosuppressants can be roughly divided into sub-categories, and can be further classified according to their mode(s) and mechanism(s) of action:

When used systemically, all immunosuppressants carry a high burden of adverse effects and increased risk of infections. This is not surprising, given the central role of the innate and adaptive immune system as the general body-defence system against infections of all kinds and other harmful effects. This is not a great consolation when there is little choice but to use such medications; the use of such medications does require a very careful, individual risk / benefit analysis and ongoing monitoring.

Allotransplantation in the past has not been an issue in oral and maxillofacial surgery, but face transplants more recently have added this theme to maxillofacial surgery, including all concomitant aspects of systemic immunosuppression. Autoimmune conditions (as many of these have oral and/or skin / facial manifestations; see below) and other inflammatory conditions have been and remain an issue in maxillofacial surgery. Fortunately, for several of these conditions topical drug delivery is a viable option, avoiding some or all of the adverse effects of systemic use of immunosuppressants (see below).

For many relevant oral and maxillofacial conditions, corticosteroids remain the first-line medications. Intra-lesion injection of corticosteroids into any condition which can be localised is the general preference for delivery.

‘Traditional agents’, corticosteroids

A number of different corticosteroids suppress the release of various different pro-inflammatory signalling molecules of a large number of different cell types, including the release of prostaglandins. The anti-inflammatory effect of corticosteroids largely results from their silencing of the genetic pathways that regulate multiple inflammatory responses. The adverse effects of long-term systemic use of corticosteroids include ulcers and bleeds of the gastrointestinal tract, hypertension (high blood pressure) and other cardiovascular diseases, increased risk of infections, myopathies (conditions affecting muscle fibres), osteoporosis (brittle bones), Cushingoid facies (moon face), cataract and glaucoma.

There are a number of oral and maxillofacial conditions where topical and/or systemic corticosteroids are used for short- and/or long-term treatments, including

‘Steroid-sparing agents’

The main types of agents that can help to reduce the dose of systemic corticosteroids when used in combination, or used as a second-line treatment option when corticosteroids do not work, are

These drugs all come with adverse effects of their own (see below).

Calcineurin inhibitors prevent the production of interleukin (a type of signalling protein involved in the regulation of the immune response) in T cells (a type of white blood cell). This results in a much diminished overall immune reaction. Examples of calcineurin inhibitors are cyclosporine, tacrolimus and sirolimus). The working mechanism of cyclosporine is similar to that of tacrolimus but the two distinct drugs bind to different target proteins. The immunosuppressive effect of tacrolimus is much greater than that of cyclosporine, and so are the number and severity of its adverse effects. Adverse effects of calcineurin inhibitors include hypertension, kidney and liver toxicity (a major problem as these agents are used to suppress donor-organ rejection after kidney or liver transplants), gastrointestinal disorders, unbalanced electrolytes and glucose levels, skin reactions and hirsutism (in women, growing a beard) and increased levels of white blood cells.

Alkylating agents (mainly chlorambucil and cyclophosphamide) are cytotoxic agents that chemically interfere with the synthesis of DNA of cells and thus block proliferation of cells. These cytotoxic properties of alkylating agents are generally used in chemotherapies of a number of haematological and other malignancies. Adverse effects of alkylating agents include an increased risk of infections and long-term development of malignancies, as well as toxicity affecting the kidneys and the cardiovascular system.

Antimetabolites (mainly methotrexate and azathioprine) are another group of cytotoxic agents that are generally used in chemotherapies of a number of malignancies. Antimetabolites pervert the cell cycle by mimicking the role of normal metabolites in cell proliferation and cause cell death by leading to faulty products and/or blocked metabolic pathways. Some antimetabolites in low dose have immuno-modulating properties. Adverse effects of antimetabolites include an increased risk of infections and long-term development of malignancies, as well as toxicity affecting the liver and the gastrointestinal tract.

Oral and maxillofacial conditions where topical and/or systemic ‘steroid sparing agents’ are used as sole drug or in combination with corticosteroids, for short- and/or long-term treatments include


This category of immunosuppressants comprises a range of proteins that are in different ways engaged in specific steps and points of the inflammatory response and / or in the development of malignancies. These agents can act as agonists (promoters) or antagonists (counterplayers) for specific targets, actions and reactions of the immune system. As such, this category of immunosuppressant agents holds some promise of more targeted effects than corticosteroids or other systemic immunosuppressants. However, there is currently not yet enough information about the long-term safety of most of these agents.

Monoclonal antibodies target a specific receptor and in this way prevent a particular reaction pathway of the inflammatory process. Different monoclonal antibodies that block

are in clinical use. Etanercept is a fusion protein (another type of antibody) that blocks the TNF-α receptor. Several types of interferons are an example of a humane cytokine (signalling molecule) with various up- and down-regulating roles in the immune system.

Generally, the adverse effects of these agents are allergic reactions, increased risk of infections (including reactivation of tuberculosis with TNF-α inhibitors), cardiovascular problems, triggering of some autoimmune syndromes and an enhanced risk to develop (or reactivate) malignancies. These adverse effects mandate strict risk/benefit considerations and careful monitoring.

Oral and maxillofacial conditions where ‘biological’ immunosuppressants are used as sole drug or in combination with other immunosuppressants, for short- and/or long-term treatments include


There are numerous unanswered questions about the exact working mechanisms of many immunosuppressant agents. These questions are the focus of much ongoing research: obviously, better understanding of these mechanisms will provide more focussed / effective treatments, hopefully at a reduced burden of adverse effects. For example, one such question in search of a convincing answer is the following. Immunosuppressant agents that are widely used to prevent donor-organ (allograft) rejections are tacitly assumed to inhibit rejection mechanisms such as cytokine (messenger molecule) release and/or proliferation, or blocking cell activation steps. However, one may also speculate that a part of their role (or perhaps even the main aspect of their role) could be the activation / stimulation of some of the body’s own immunosuppressant molecules and mechanisms. That is an aspect which clearly has an impact on how to best make use of such agents, and how to search for new and improved such agents. These then could be less blunt and much better tailored for particular tasks (ever the optimist!).